For much of the 21st century, the long-running ABC medical soap series Grey's Anatomy has dominated the television landscape. As of season 14, the drama has aired over 300 episodes, joining an exclusive club of hour long dramas that have made it that far.

Within those hundreds of episodes, thousands upon thousands of characters have been featured, ranging from the central characters whose stories viewers have been obsessively invested in for over a decade, to the guest starring love interests and bad guys and patients who come in to shake things up.

Given how many characters there have been, and how long the series has been on the air, it's only natural that there have been dozens, if not hundreds, of love stories along the way.

Some of them have meant more than others, while some have been entirely inconsequential in the long run.

However, above all, there have been 20 main love stories that have captured viewers' attention over all these years.

Whether you loved them or hated them, this group of couples is truly in a class of their own. But when it comes to writing, acting, and natural chemistry, not all couples can be created equal.

Here is Every Major Grey's Anatomy Couple Ranked.

20. Derek and Addison

From nearly the beginning of the series, Grey's made it abundantly clear that it wasn't particularly a fan of marriages -- or, at least, totally functional and healthy ones.

You'd have to look no further than the horribly chaotic, dysfunctional marriage between leading man Derek Shepherd and his previously unfaithful wife Addison Montgomery to get a glimpse of that.

Much of the series' first season's developments hinge upon the fact that Derek has left Addison behind, due to her infidelity with Derek's own best friend. While the couple may have only been separated at that point, it's also beyond clear that the show never truly considers a reconciliation of this toxic union a real possibility.

It's for the better of both characters and the series as a whole that their relationship goes down in flames as spectacularly as it does.

The official dissolution of their marriage allows Derek to move on to be with Meredith, and Addison to move on to bigger and better love interests - and a series of her own in Private Practice.

However, the lasting damage from their marriage, and how horrible they were to one another, is a stain on the series as a whole from the very beginning.

19. Owen and Amelia

Unfortunately, Derek isn't the only Shepherd who gets mired within a toxic marriage that doesn't seem to ever have a future.

For some unthinkable reason, in recent years, Grey's has decided to pair together two characters who could not have been more incompatible. Both scarred by damaged pasts and issues well beyond their own control, Owen Hunt and Amelia Shepherd were seemingly paired together out of the series' uncontrollable need to find everyone a mate.

Since the couple has been together, they have taken viewers on a true roller coaster, and not an enjoyable one in the slightest.

With differing views on their future, their inability to agree on anything constructive to creating a healthy relationship, and their misguided marriage, Owen and Amelia have spent far more time together crying and fighting and splitting up than existing as a functional romantic unit.

Making matters worse is the clear lack of any form of chemistry on screen between series veteran Kevin McKidd and Private Practice transplant Caterina Scorsone.

Grey's Anatomy has had its fair share of misguided romantic relationships devoid of any noticeable chemistry, but so far, Owen and Amelia may just be the worst of them all.

18. George and Callie

When it comes to misguided marriages that never should have happened, however, the short-lived marriage between George O'Malley and Callie Torres probably takes first prize.

The unlikely couple were genuinely adorable to begin with, having the most meet-cute of origins as Callie tended to an ailing George when he dislocated his shoulder in season 2. However, by season 3, things had dramatically escalated for the only briefly dating duo.

Following George's father's passing, they decided to hightail it to Vegas and get married. Like most things that happen in Vegas, this decision should have stayed there.

When the newlyweds came back to the reality of Seattle, things would only continue to get worse for them. Things really reached a head, however, when a drunken George slept with his then best friend, Izzie.

What began as a drunken mistake, however, soon turned into a full blown realization of what they then believed to be love. Of course, as soon as Callie learned about all that had gone on, it was abundantly clear that there was even less of a future in this relationship than there had been before.

So, thankfully, the couple divorced in season 4, putting an end to one of the worst coupling decisions the series has ever made.

17. George and Izzie

Unfortunately, following the dissolution of one dreadful George O'Malley relationship, the series doubled down on its commitment to producing yet another.

After George and Callie separated, he attempted to pursue a romantic relationship on a grander scale with best friend Izzie Stevens. It truly is a mystery why the couple never worked in any way.

For the entire run thus far, they had always worked wonderfully off one another in terms of best friend chemistry, growing closer and closer to one another with no real displays of awkwardness or concerns about intimacy.

However, once romantic and physical intimacy entered the picture, things took a turn for the worse.

Thankfully, the attempted couple soon caught onto that themselves, as they realized they were much more suited for the close companionship role of best friends rather than romantic partners.

After multiple awkward attempts at making a go of a romantic relationship, they accepted the fact that the chemistry just wasn't right, and went back to being the friends they had always been up until that moment.

George would even go on to walk Izzie down the aisle at her wedding, proving that there was no lingering awkwardness or resentment there between either parties.

16. Jackson and Maggie

Apparently, in the world of Grey's Anatomy, nothing says romantic like becoming involved with someone who is now sort of your step-sibling as a result of your parents' recent marriage.

Jackson Avery and Maggie Pierce, children of the now married Catherine Avery and Richard Webber, have recently found themselves at the center of a hotly debated storyline in which they've been struggling to navigate their attraction to one another, given the fact that, in some way, they are essentially family.

Admittedly, it's not quite a cut and dry scenario: Richard is Maggie's biological father, but he had nothing to do with her upbringing.

However, nevertheless, the awkwardness -- as well as the considerable ick factor -- remains.

It's hard to conceive of why the series proceeded with pursuing this relationship at all -- this is Grey's Anatomy, not Game of Thrones -- but making matters worse is the lack of chemistry shown between Jesse Williams and Kelly McCreary in each of the scenes clearly meant to be building romantic tension.

Grey's would be better off by far trying to put this relationship behind them for good, even as it finds itself struggling to find a central romantic relationship.

15. Alex and Izzie

Sometimes, it's tempting to pair two characters together when they're both young, attractive, and seem to have nothing in common with one another. Opposites can attract and combative personalities can lead to sparks that are worth pursuing.

However, it's almost never a good idea to put these two types of personalities in a long term relationship -- and it's an even worse idea to have them get married.

Take, for example, the horribly developed relationship between Izzie Stevens and Alex Karev. From the beginning of the series, he treated her horribly, demeaning her at every turn.

Somehow, eventually, she gave into his badgering, and the two became a casual fling with no real signs of ever progressing to anything more.

Eventually, after losing respective loves, they sought ill-timed solace in one another. And unfortunately, this poorly thought out moment of convenience led to their coming together as a properly committed couple for the first time.

However, rather than taking their time with things, and realizing that their behaviors and personalities were truly incompatible, they rushed into getting married, only to divorce a year later as a result of Katherine Heigl's unceremonious departure from the series.

From beginning to end, their relationship was sloppily written, leaving Alex with plenty of emotional baggage to wrestle with in Izzie's eventual absence.

14. Jo and Alex

Unfortunately for Alex, the next big romance he would find himself with after Izzie wouldn't exactly be that much easier on him in terms of its immense emotional baggage.

For the last few years, Alex has been in a relationship, on and off, with Jo Wilson, who is now his fiancée -- except their relationship has never really run anything remotely resembling a smooth course.

Some of the questionable relationship's most noteworthy moments have included flares of jealousy that have resulted in assault and near convictions due to miscommunication, along with lies upon lies that have culminated in the reveal of a forged identity due to being on the run from an abusive spouse.

Jo's character could have been handled well, had each and every part of her story not been sensationalized and turned into something worth stigmatizing further for the sake of soap opera drama.

However, as a result of the poor way in which her history of abuse and trauma has been unfolded and touted as scandalous, her character feels cheapened, and their relationship all the more difficult to stomach as a result of it.

In addition, as appealing as the on screen duo of Justin Chambers and Camilla Luddington may be to the eye, there has just never really been any sort of believable spark between them, even as they find themselves now headed toward marriage.

13. Mark and Addison

While some of these previously mentioned couples may have been lacking in chemistry or spark, that was definitely never the case for the relationship (if one could even call it that) between Mark Sloan and Addison Montgomery.

In fact, an abundance of chemistry and heat may have, in fact, been this dynamic's downfall, as their inability to control themselves around each other on multiple occasions proved detrimental to much of their lives in the end.

Their relationship with one another was primarily in the bedroom, and led, in large part, to the end of Addison's marriage to none other than Mark's best friend, Derek Shepherd.

When they were together, they were all but entirely focused on their own interests and their own gratification, which made them such a disastrous pairing when they tried to imagine anything more serious happening in the future.

That's not to say that there weren't ever any real emotions between them, however, as there most certainly were. There was even the matter of an unplanned pregnancy that Addison would ultimately abort.

However, in the end, no matter how compatible they were with one another in physical ways, they were forced to realize that that was all it would ever be between them.

They would always have wandering eyes if they were together, and they both deserved better than what Addison herself referred to as a booty call.

12. Owen and Cristina

When one of the earliest significant moments in a relationship is one half of a couple suffering from PTSD and nearly choking the other out as a result of a PTSD dream, that's probably a good sign that the relationship is never going to last.

The romantic pairing of Afghanistan veteran Owen Hunt and surgical genius Cristina Yang was polarizing from the beginning, but the series remained committed to pursuing the possibilities of developing them into something more all the same.

By season 7, the couple was married, but soon enough after their marriage, it became apparent that things were not going to go well for the ill-matched couple.

The first real source of conflict for their marriage would prove to be the greatest and ultimately insurmountable one for them.

Their hopes for their future as a couple were so different, and could be boiled down to one simple, but significant difference in point of view: Owen wanted children, and Cristina never did.

At one point, Cristina even became pregnant, but chose to abort the pregnancy instead. This proved a real source of resentment for Owen, who would eventually begin to cheat on Cristina.

As they continued to be unable to reconcile their points of view, the pair would eventually divorce, briefly attempting to rekindle what they once had before realizing once and for all that they were better off apart than they ever were together.

11. Richard and Ellis

It's the relationship that launched an entire series: the affair between Richard Webber and Ellis Grey during their medical residency arguably set the course for the future that allowed Meredith's life to unfold the way in which it has.

Despite both being married at the time, to Adele and Thatcher respectively, Richard and Ellis found themselves drawn to one another, and even intended to leave their respective spouses and be together for real.

However, even though Ellis went through with leaving her husband, Richard chickened out and stayed with his wife, not wanting to be with someone who would exceed him in his career forever.

The fallout of their relationship was devastating all around. Ellis attempted to commit suicide as a cry for Richard's attention and an attempt to win him back, even doing so in front of a young Meredith, which scarred her permanently.

She would then learn that she was pregnant with Richard's child, keeping the baby girl a secret all throughout her pregnancy and giving her up for adoption.

Later in life, when she developed Alzheimer's, Ellis reconnected with Richard through his visits to spend time with her in her nursing home, the two of them reminiscing fondly -- albeit wistfully -- on their past and the life they could have had together had things gone as planned.

10. Denny and Izzie

Grey's Anatomy has a problem that isn't unique to its series by any means, but it is, however, an all too common problem for it in particular.

Its tendency to revisit relationships that were enjoyable in part to begin with, only to twist them in some way that taints all enjoyment of it in any form, is something the series has done quite a few times.

However, perhaps the most egregious example of that comes in the form of Izzie Stevens' romance with Denny Duquette. Although problematic in its initial form, their story initially represented a compassionate nurse falling for a sickly patient and vice versa.

When the series decided to revisit their relationship a few seasons later, though, in the form of Izzie fantasizing of a romantic relationship with Denny's ghost, suddenly, any moment that had previously been enjoyable went all but out the window.

Katherine Heigl and Jeffrey Dean Morgan did manage to recapture their earlier chemistry in these moments, but the overall nature of messy discomfort that came with this twisty, turny supernatural reveal just became too much for many viewers.

What Denny and Izzie once had was heartbreaking in its brevity and the impact it left. However, by returning to their relationship, in so poorly conceived a form, the series undid any good that it had once created.

9. Callie and Arizona

When it comes to promoting LGBTQ acceptance and representation, Grey's Anatomy was one of the first primetime drama series to feature series regular characters who identified as a member of the LGBTQ community.

Most notable of all was the decision to include the relationship between the bisexual orthopedic surgeon Callie Torres and Arizona Robbins, a pediatric surgeon who also happened to be a lesbian.

Their relationship was a breath of fresh air for the series when it began, finally offering the long-suffering Callie a romantic relationship that was healthy and happy and fully reciprocated.

However, over time, their relationship began to sour, growing uglier and uglier as the seasons went on.

Following the plane crash at the end of season 8, Callie and Arizona began to grow distant. Callie makes the decision to have Arizona's leg amputated, which leads the couple to become cold toward one another.

When a visiting female doctor shows a romantic interest in Arizona, she finds herself falling for her, and engages in a brief fling since she finally feels wanted again. After Arizona's infidelity, the couple take part in therapy and get every ugly feeling out in the open.

However, with everything out there, it proves hard for the couple to move beyond it. Soon enough, they divorce and engage in an ugly custody battle, before ultimately deciding to split custody even as Callie moves away to be with her new girlfriend in New York.

8. Jackson and April

Grey's Anatomy has always been interested in pairing the unlikely characters together in romantic scenarios, no matter the shocking or uncomfortable outcomes that may follow as a result of it.

Prim and proper Christian girl April Kepner began the series as one of the most difficult characters to figure out. Enter openly spoiled rich kid Jackson Avery, who took it upon himself to break down the closed off April's walls and work his way into her heart and beyond.

Over time, April opened up more and began to express herself more freely as a result of her relationship with Jackson, no matter how messy it would prove to be.

Over the course of their frequently on again and off again relationship, April would find herself running out on her own wedding to another man to be with Jackson, the two would get married and divorced themselves, they would lose a child, and welcome another, and find themselves growing further and further apart as April struggled with a crisis of faith.

As Sarah Drew is scheduled to exit the series with season 14's finale, it's hard to exactly imagine what the future holds for these two.

However, it seems pretty clear that a happy ending isn't in the cards for them, no matter what they've been through and how much they have helped each other to grow.

7. Teddy and Henry

As it turns out, Denny and Izzie haven't been the series' only foray into the relationship between a doctor and patient. However, while the relationship between Teddy Altman and Henry Burton certainly had a less than normal beginning, its development and ultimate culmination proved far more successful than what Grey's tried to do with Denny and Izzie.

When Teddy and Henry met, he was an ailing patient without insurance. Teddy, being altruistic and a doctor, made the bold offer to marry Henry in order to offer him her life insurance.

However, it was made clear that this was purely a business-minded arrangement, and no romantic relationship would be involved, despite their marital status.

However, as always happens in situations where people agree that they won't fall in love with one another, the two slowly began to realize the extent of their mutual feelings for each other, even as Teddy had continued seeing other people to convince herself nothing was there with Henry.

Unfortunately, by the time they had both allowed themselves to be open and honest about their respective feelings, Henry had become plagued by another medical condition from which he couldn't be saved, no matter the earnest attempts of Cristina and Richard.

As is so often the case on Grey's, yet another heartwarming love story never got the full exploration it deserved.

6. Ben and Bailey

Grey's has shown itself, time and again, to not really be all that much of a fan of marriage in the long run. Most marriages are either beset by abuse, infidelity, prolonged conflicts of belief, and ultimately bitter separation and divorce.

However -- so far, at least -- one wonderfully married couple stands out among the rest: Miranda Bailey and Ben Warren.

After Miranda's own toxic first marriage, Ben was truly the breath of fresh air that she needed in her life. Optimistic and supportive and always interested in her point of view, Ben has always been shown as the perfect partner to balance Bailey's obsessive neuroses and incredibly driven demeanor.

In the past, Ben had been a medical resident in California, which posed a challenge to the couple as he was forced to commute back and forth between California and Seattle.

Nevertheless, they married, and he has been nothing short of a wonderful father to her son, Tuck.

In recent episodes, however, Bailey has been shown to be struggling with Ben's decision to become a firefighter, as he is now the lead of the spinoff firefighter series Station 19. We can only hope that these two make it through whatever it is Shondaland intends to throw their way.

5. Burke and Cristina

Sometimes, love stories don't get the happy ending they deserve, and it's entirely out of the characters' control. The relationship between Preston Burke and Cristina Yang was one of the series' earliest and most passionate.

Despite rules in place about interns and residents becoming romantically involved, the two found themselves drawn to one another despite themselves and began to engage in a secret fling with one another.

Their brief involvement with one another resulted in Cristina becoming pregnant -- but before she even knew what she wanted to do, she found herself passing out, learning that it was an ectopic pregnancy that would have to be aborted.

After the heartbreaking way their first attempt at a relationship ended, the two decided to give it a proper try, realizing that they cared for one another far more deeply and moving in together early in season 2.

When Burke was shot and found himself struggling with a tremor in his hand as a result of the damage, Cristina helped him during his operations, serving as his support and guiding him.

They were brilliantly matched, totally compatible, and even intended to be married by the end of season 3.

However, due to Isaiah Washington's departure from the series, Burke was written to leave her at the altar.

Years later, though, upon Sandra Oh's own departure from the show, the couple had a reunion of sorts, as Burke invited Cristina to Zurich to serve as his replacement in the position he was vacating.

4. Richard and Adele

If the affair between Richard Webber and Ellis Grey was the relationship that made Grey's Anatomy possible, then the long-standing marriage between Richard and Adele Webber should receive just as much of the credit.

Credit should especially be given to the almost saintly Adele, who stood by Richard's side for much of his life despite being aware of his infidelity.

Even as she knew about her husband's unfaithfulness, she chose to stand by him, because she loved him and knew -- or, at the very least, could only hope- - that he would choose to stand by her in return.

Yet even as she stuck with him through all the emotional pain he caused her, she ultimately left him upon his refusal to retire when she asked him to.

They ultimately reconciled under the most startling of circumstances: Adele would learn that she was pregnant with Richard's child, despite being well into her middle age, but ultimately, she would lose the baby.

Medical tragedies would continue to test the couple's commitment to one another, as Adele would soon be diagnosed with Alzheimer's, even eventually forgetting Richard altogether. He continued to visit her whenever he could once she had been placed in medical care, but even that would not last long as Adele soon passed away due to a heart attack as a result of an aneurysm.

Following her demise, Richard attended the wedding of Ben and Bailey, reflecting on his own wedding with Adele and imagining the two of them dancing to "My Funny Valentine."

3. Derek and Meredith

When they met, they were just a boy and a girl in a bar. But from the moment their story began, it was always clear that Meredith Grey and Derek Shepherd were destined to be something so much more.

It took them a few gripping, tense seasons to get to that point, given all the soapy drama that the series threw their way. However, by the time the relationship affectionately known as MerDer came together as a real couple, their place as the rightful reigning couple in the series had been well solidified.

Over the course of their relationship, they would overcome many obstacles, which allowed them to reach many of the requisite milestones for important television couples.

But every milestone they reached, they handled in their own way. Whether it was their Post It note wedding ceremony, the decision to adopt little Zola and the second hurried wedding that came with it, or their attempts to navigate working in different locations and long distance trips, they always handled everything as a team, with unique heart and warmth.

In the later years, they faced more difficulties than ever before, realizing that, at times, their dreams lay at odds with one another.

However, no matter how difficult that may have been, nothing can compare to how senselessly Derek was killed off in the name of revitalizing the show.

It's safe to say, at this point, that without his character, and this core relationship, around, the show has never felt quite the same.

2. Meredith and Cristina

Sometimes, the strongest love stories aren't romantic. Meredith and Derek's relationship may have been the heart of the series for much of its run, but it was the love story between two brilliant, brave, beautiful women that set the show apart from so many other dramas on air.

Meredith Grey and Cristina Yang were drawn to one another from day one as medical interns, and as the years went on, as hearts were broken and careers were changed and health scares came and went, they were always there for one another, unflagging in their support and comfort.

They were, as they so often said, each other's person. When the worst happened, they were there to build each other up again. When the best happened, they were the first person one turned to in order to celebrate.

Their life goals weren't the same, but they never tore one another down because of it. They lifted each other up and encouraged each other to pursue their dreams no matter what.

When it came time for Cristina to depart the series, and Meredith was at a difficult place in her marriage with Derek, Cristina left her with strong words of encouragement that only a true friend could offer: “You are a gifted surgeon with an extraordinary mind. Don't let what he wants eclipse what you need. He's very dreamy, but he is not the sun. You are.”

It's heartfelt, unflinching honesty like this that made their love for one another so inspiring, so important, and so one of a kind.

1. Mark and Lexie

As we've already seen plenty of times so far, even the strongest of love stories in the world of Grey's Anatomy aren't guaranteed their happily ever after. This can be seen most clearly -- and most tragically -- in the case of the eternally star-crossed relationship between Lexie Grey and Mark Sloan.

On paper, the pair seems like absolutely nothing about them should make sense.

In addition to the considerable age difference between them, Lexie and Mark couldn't have been more different in terms of personality -- with Lexie being portrayed as all heart and intellect, and Mark always portrayed as a man of bravado and gratification.

However, somehow, the pair represent the perfect model of opposites not only attracting, but completing one another.

From the moment Little Grey asked Mark to teach her, to his promise to her that she was the one who put him back together, it was beyond clear that these two unlikely lovers were meant to be together. Mark and Lexie both even say as much themselves -- but unfortunately, it's in their final moments together.

Weighed down by bad timing and the inability to accept their feelings until it's much too late, Mark and Lexie find themselves with the most tragic of all couples' endings in the series, as Lexie dies in the plane crash with Mark by her side, and Mark dies soon after back in Seattle.

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Which Grey's Anatomy couples have you been the most invested in? Let us know in the comments!