Grey's Anatomy has been on the air since 2005. Throughout fifteen seasons, it has captivated audiences and been a constant in several viewers' lives. The series is the longest-running medical drama on TV and overall, one of the most famous shows ever. Everybody knows of Grey's Anatomy, even if they haven't actually seen it.

This series is completely iconic, and still manages to be extremely successful, even after many of the original main characters have long since been written out of the show. To maintain its massive success, Grey's must be doing something right, and that something is its relationships.

The drama, friendships, and romances consistently keep fans coming back for more, no matter how many heartbreaking breakups they've had to endure throughout Grey's fifteen seasons. With as many powerful relationships as this show has and has had in the past, there have been just as many breakups that have altered the show and destroyed fans hearts. Let's take a look at 10 of Grey's Anatomy's hardest-hitting breakups.

10. IZZIE STEVENS AND ALEX KAREV

Izzie and Alex embracing at their wedding in Grey's Anatomy

Grey's Anatomy's massive success began to dwindle upon Izzie Stevens' departure from the show, which had been caused by a feud between actress Katherine Heigl and show runner Shonda Rhimes. The infamous feud aside, Izzie Stevens was one of the most compelling characters ever to appear on Grey's, and is still a fan-favourite to this day.

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Not only did her exit serve to hurt the show, but her break-up with Alex Karev also drastically upset the fanbase. Izzie and Alex had an ongoing romance for a while, and fans absolutely loved it. So when the show began to threaten that beautiful dynamic - and ultimately destroy it in the most disrespectful way - viewers were understandably devastated.

9. JACKSON AVERY AND APRIL KEPNER

Jackson and April kiss in Grey's Anatomy

Jackson and April were the dream team. Though they had a rollercoaster-ride of a relationship, and were the source of plenty of drama, many fans adored this pairing. By the time Grey's decided to put the axe to this longterm romance - and ultimately, write the beloved April Kepner out of the show - fans had been through so much with the couple that the demise of their bond was very upsetting.

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Jackson and April's dynamic, combined with Sarah Drew and Jesse Williams' undeniable chemistry, made fans root for these two passionately. Through their transition from friends to lovers, their first breakup, Jackson interrupting April's wedding to tell her his true feelings and them running away together and eloping, to the death of their infant son and the birth of their daughter...many viewers really just wanted to see Jackson and April work it out, but ultimately, Grey's Anatomy crushed that dream.

8. MARK SLOAN AND LEXIE GREY

McSteamy was one of Grey's most iconic characters. He first appeared in season 2, and enthralled audiences immediately with his charm and arrogant yet endearing demeanour. When Meredith's little sister, Lexie, was introduced late in season 3, this pairing seemed unlikely.

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But despite their age gap and very different personalities, when Lexie and Mark struck up a romance, it was clear that they were meant to be together. And ultimately, they did end up together, but after much drama and a tragic plane crash that claimed both their lives. Mark and Lexie will forever be one of the most tragic romances Grey's has ever presented.

7. CRISTINA YANG AND MEREDITH GREY

Though this was not technically a break-up - at least not a romantic break-up - Cristina Yang and Meredith Grey had what is regarded by most as the most iconic friendship on Grey's Anatomy. The dynamic these two had started in Grey's pilot episode, and their bond grew from there, until eventually they became each other's person.

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In season 10, Cristina leaves Grey Sloan Memorial for a job in Switzerland. Her final season is a heartbreaking one, which in many different episodes, presents Cristina debating certain aspects of her life, such as her romance with Owen. At the end of the season, Cristina leaves for Switzerland, after one last "dance it out" session with Meredith. Cristina's departure was arguably one of the most heartbreaking instances on the show, and this was largely due to the fact that fans had to say goodbye to Meredith and Cristina's amazing friendship.

6. ALEX KAREV AND REBECCA POPE

Alex comforts Ava at the hospital

Alex Karev has been through a lot. Establishing his reputation as the bad boy who is a bit of an ass but actually has a heart of gold, early on in the series. For a character that Shonda Rhimes didn't even create until the pilot episode was already primarily filmed, Alex has become one of the most successful and beloved of the entire series. In season 3, Alex heroically saves a woman who is trapped under a large piece of metal after a tragic ferry boat crash. But his noble action has some damaging consequences, as the woman he saves has amnesia, identity issues, and later on, is revealed to be extremely mentally ill.

5. PRESTON BURKE AND CRISTINA YANG

Cristina confronts Burke at a wedding in Grey's Anatomy.

Preston and Cristina were one of the first romances Grey's created, and their relationship was off to a rocky start right from the beginning. Cristina suffered an ectopic pregnancy early on in their relationship, and the seasons leading up to Preston's ultimate departure, would prove to be a dramatic rollercoaster for the couple. In season 3, the two decided to get married, but this would prove to be a fatal error for their relationship. The season finale revolved around the wedding, and by the end of the episode, it was revealed that Preston had run out on Cristina.

4. ADDISON MONTGOMERY AND MARK SLOAN

Mark Sloan and Addison Montgomery in Grey's Anatomy

Addison's affair with Mark was a big part of the show for the earlier seasons. This relationship was a destructive one, undoubtedly. It fed into destroying Addison's marriage to Derek, and temporarily presenting a rift and feud between Mark and Derek, who had been best friends since they were kids.

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The biggest repercussion that Addison and Mark's break-up had, was Addison's ultimate departure from Grey's Anatomy, and her transition to the spin-off, Private Practice. It was great to see Addison get her own show, but she was sorely missed by the Grey's fanbase.

3. MIRANDA BAILEY AND TUCKER JONES

This break-up may not have had much effect on the audience, but it was devastating for Miranda Bailey. The couple's son was a toddler back then, and while their relationship had always been a little rocky due to Bailey's busy work schedule, the break-up was pretty intense.

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Shortly after an incident that put Tuck Jr. in the hospital, Dr. Bailey and Tucker Sr. began to have some serious problems, and their ultimate divorce would hurt Bailey greatly.

2. RICHARD WEBBER AND ELLIS GREY

Richard Webber and Ellis Grey in Grey's Anatomy

Ellis and Richard's relationship - though seen mostly through flashbacks - was one of the most crucial to the show. Their romance started when they were to young interns at Seattle Grace. They were both married, but they fell for each other nonetheless, and this was the beginning of a romance that would shape the show into what it is.

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Ellis and Richard's relationship still plays a role in the show today - even now that Ellis is deceased - and Meredith would not be who she is, had it not been for their break-up.

1. CALLIE TORRES AND ARIZONA ROBBINS

Callie was one of the most captivating, iconic characters that ever existed in the Grey's Anatomy universe. Being introduced early in the second season, Callie had a whirlwind romance with George O'Malley, and later came out as bisexual, beginning a romance with Arizona in season 5.

Callie and Arizona had an absolutely epic love story, one that provided LGBTQ+ reputation and captured fans hearts for several seasons. This meant that their heartbreaking separation and divorce would serve to completely devastate viewers, and the loss of these two characters and their beautiful relationship, is one of the most impactful Grey's losses to date.

NEXT: Every Sizzling Season Of Grey's Anatomy So Far, Ranked