The 10 Most Devastating ‘Grey’s Anatomy’ Breakups That Still Hurt — Ranked by Pain Level

Few television series have mastered the act of balancing plot drama and soul-crushing relationship heartache quite like Grey’s Anatomy has. In its twenty years on air, the medical drama has gone through so much. From intense and memorable surgeries to jaw-dropping disaster episodes and medical anomalies. But in between all of that are whirlwind romances that capture the hearts of viewers and refuse to let go, even when they sting. Grey’s Anatomy truly has something for everyone in the romance department. From love affairs — whether it be with a co-worker or a patient, to slow-burns that unravel over multiple seasons, and first loves that you can never truly forget.

But with every successful romance on Grey’s Anatomy, there’s often an imminent, devastating breakup that follows. No relationship is safe. Not the fan-favorite couple who seemed destined for the long haul, not the couple that has been together since the early seasons, no one. Fans know by now not to get their hopes up when it comes to those who populate the halls of Grey Sloan Memorial, but it’s still painful to look back on the romances that were and see how they crumbled before our very eyes.

10Jackson Avery and Stephanie Edwards

In Season 9, Jackson (Jesse Williams) started up a romance with Stephanie Edwards (Jerrika Hinton), who was an intern at the time. Their relationship began shortly after he and April (Sarah Drew) called it quits and decided to be friends. But fans knew that there were still feelings between them. Still, April went on the get engaged to a paramedic named Matthew (Justin Bruening), and invited Stephanie to the wedding in a show of friendliness and acceptance of her relationship with Jackson.

Jackson attended the wedding as Stephanie’s plus one, and it was meant to be a great day, but it quickly turned sour when Jackson stood up mid-wedding and confessed his love for April. The two ran out of the wedding together, leaving their respective partners behind. Stephanie and Jackson weren’t together for very long, but they were really sweet together, so it’s just sad that their breakup happened in such a public way, with no warning for her. How was she to know that Jackson would interrupt a wedding? It doesn’t happen often. Even in the world of Grey’s Anatomy.

9Atticus “Link” Lincoln and Amelia Shepherd

Link (Chris Carmack) and Amelia (Caterina Scorsone) began their romance in Season 15, with what began as a casual fling. It quickly became serious when Amelia discovered she was pregnant. This was an emotional moment for her after her first son was born with anencephaly and didn’t make it. Link stood by her through it all, and together they welcomed their son Scout in Season 16. They made a great couple for a little while, but Amelia’s history of commitment issues had her doubting their compatibility long term.

This came to a head in Season 17 when Link proposed to her. She turned him down, not because she didn’t love him, but because she didn’t want to say yes out of obligation or for fear of losing him. Unfortunately, that ”no” left Link heartbroken, and the pair split up. They remain loyal co-parents to Scout, but there’s still lingering tension that may never quite resolve itself.

8Meredith Grey and Derek Shepherd

Meredith (Ellen Pompeo) and Derek (Patrick Dempsey) are THE couple of the show, but they weren’t always so solid. Their whirlwind romance begins in the very first episode with a one-night stand, only for Meredith to discover to her horror that he is her new boss. They end up falling in love and beginning a relationship anyway, and it’s going great, until the Season 1 finale, when a woman named Addison (Kate Walsh) shows up and drops the bomb on Meredith that she is Derek’s wife. This kicks off a love triangle for the next season, and also gives us the best line of Grey’s Anatomy: “Pick me. Choose me. Love me.”

They eventually get back together in Season 3, but there are so many mini breakups and breaks that they take before they are officially solid together. The only other “official” breakup they have is in the Season 3 finale at Cristina’s (Sandra Oh) would-be wedding to Burke (Isaiah Washington), but by the Season 4 premiere, they are in a casual relationship again because of a time jump. From Season 5 onwards, the pair are solid though, and remain so until Derek’s death in Season 11.

7Owen Hunt and Cristina Yang

Owen Hunt (Kevin McKidd) is hands down the most disliked character on Grey’s Anatomy, so when he was paired up with Cristina, who is one of the most beloved, fans were concerned. Turns out that concern was rightfully placed, because their relationship was full of turmoil from the get-go. Their relationship started out fine enough, but their poor communication skills made things difficult. They also have very different stances on having children. They ultimately get married in Season 7 after the hospital shooting, but that was partially a decision that stemmed from Cristina’s PTSD.

They split in Season 9 after a messy couple of seasons. Owen ended up cheating on her, and she made him tell her the details. He never forgave her for getting an abortion, despite knowing she never wanted children. They fought constantly. They loved each other deep down, but they were never able to make it work. Still, their divorce was tough to watch. The scene of them signing the papers is one of the show’s saddest as they both break down in tears and share one final kiss afterward, signaling the end of one of the show’s pinnacle couples.

6Izzie Stevens and Alex Karev

Izzie (Katherine Heigl) and Alex’s (Justin Chambers) road to romance started off rocky. Early-season Alex was, frankly, a jerk. Alex Karev was pompous, cruel to pretty much everyone he talked to, and he was immature. Though there was attraction between them, Izzie was never able to take him seriously. They eventually became close friends, but they didn’t start dating until Season 5. During that same season, Izzie was diagnosed with stage 4 cancer. They decided to get married, since Izzie was unsure if she’d make it through, and she had always dreamt of getting married.

After she recovers from her cancer, she is fired from the hospital after a mistake with a patient, and leaves town, believing that Alex sided against her. In turn, Alex feels abandoned since she didn’t tell him that she was leaving or give any explanation. He’s left heartbroken. And when she does finally come back, he’s unable to fully forgive her because he realizes he can’t trust that she’ll stay, and he’s realized he deserves someone who will be there for him, prompting them to split for good. At least until Season 16, but we’ll get to that.

5Cristina Yang and Preston Burke

When we first meet Cristina Yang, she is no-nonsense, laser-focused on her work, and won’t let anything or anyone get in the way of her achieving greatness. So when she meets Preston Burke, the attending cardiothoracic surgeon, she’s thrilled that she’ll be able to really hone in on her chosen specialty. What she doesn’t anticipate is falling for him. The pair has a whirlwind romance. It’s much more lowkey than Meredith and Derek, who were the other intern/attending romance at the time, but they’re just as sweet to watch.

However, their breakup is really sad — albeit, slightly hopeful. Cristina gives everything to Burke; she does his surgeries for him when his hand is unusable, which gives her firsthand knowledge that you can’t put a price on. However, he gets all the credit for it. When they get engaged, she fashions herself to be the perfect bride and wife for him. She’s all set the marry him and start their lives together, but then he leaves HER at the altar. She returns to their apartment in disbelief to find that he has packed up all of his things and is gone, and in one of the show’s most heartwrenching moments, she cries out “I’m free” and gets Meredith to cut her out of her wedding dress — allowing her to reclaim the piece of herself that she lost.

4Lexie Grey and Mark Sloan

Lexie (Chyler Leigh) and Mark (Eric Dane) were meant to be together; it was clear from the moment they met. And the time they were together, it was beautiful. But their age gap caused a lot of strife in their relationship. Well, that, and Mark’s past womanizing ways. Their breakup came in Grey’s Anatomy Season 6 when Mark’s pregnant teenage daughter from a past relationship (whom he didn’t know about) came to live with him, and Lexie understandably wasn’t ready to be a step-mom or a step-grandmother yet. They briefly rekindled their romance, but then it came out that Callie (Sara Ramirez) was pregnant by him, and Lexie ended things again, asking him, “How have you gotten me into this situation twice?”

From then on, they continued to have a lot of longing looks and will-they-won’t-they moments, but alas, it would never be. Their story ends in the most tragic of ways. They are both on the fatal flight in the Season 8 finale, and both succumb to their injuries from the crash. Lexie dies with Mark holding her hand and telling her that he loves her, and that they are “meant to be.” He dies shortly after in the Season 9 premiere. Their love story was so meant to be, they even went together in death. It’d be romantic if it weren’t so darn sad.

3Callie Torres and Arizona Robbins

Callie and Arizona (Jessica Capshaw) are one of the longest couples on the show, so the fact that they even make the list is devastating enough on its own. The reasoning behind their breakup just adds insult to injury. They meet in Season 5, when Arizona sweeps Callie off her feet. They’re a beautiful love story of finding someone when you least expect to, and also finding yourself. They overcame some big obstacles in their relationship, like Callie still being close friends with Mark, and Arizona’s initial reservations about having children. But through good communication and deep love for one another, they made it work. Until Season 8. The plane crash was a reset for Grey’s Anatomy in every single way possible.

Arizona lost her legs after the plane crash, which caused her a lot of trauma, and caused her to resent Callie. This resentment led to her cheating on Callie with a visiting doctor during the superstorm episode, which Callie found out about almost immediately. They tried couples therapy and even a trial separation, but neither worked, and they realized it was best to go their separate ways. It doesn’t end there, though. A horrifically messy custody battle ensued, where both parties played dirty. Even though they eventually came out the other side as friends and co-parents, they’ll never be the Callie and Arizona we once knew and loved, and it’s so disappointing.

2Jo Wilson and Alex Karev

Jo (Camilla Luddington) and Alex meet in Season 9 and bond over difficult pasts. Immediately, you can sense a connection between them, but it takes them a bit to fully build their attraction into something stable. It isn’t until Season 12 that they are a proper couple, and in Season 14, they get married. Jo can be credited a lot for helping Alex become the character that fans grew to love. His character growth from Season 1 to the later seasons is night and day.

Their breakup, though, is one that came completely out of left field and remains the most shocking and baffling moment in the show to date. In Season 16, Alex up and left Seattle without warning. Instead, he left letters behind for Meredith, Bailey (Chandra Wilson), and Jo. In the letters, he reveals that he reconnected with Izzie and that sometime over the past 10 years she had used the embryos they froze during her cancer treatment, and has been raising twins. He drops the bomb that he has decided to move to Kansas to be with Izzie and their kids. It’s a jaw-dropping reveal, especially after all that we saw him go through with Izzy, and how deeply in love he was with Jo. To just leave her in a letter was diabolical, and it left Jo — and fans — blindsided.

1Jackson Avery and April Kepner

Many of the couples in Grey’s Anatomy were torn apart by cheating, death, or ex-wives. However, Jackson and April stand out because their relationship deterioration came from unimaginable grief. Jackson and April didn’t get along at first, as their personalities often clashed. But they grow closer, especially after the hospital shooting, and eventually become roommates. Feelings started to emerge between them, but it wasn’t until the episode where they were taking their boards that something finally happened between them. They struggled to cope with their feelings for one another while dating other people, but ultimately couldn’t, resulting in Jackson confessing his love to her at her wedding to Matthew and the pair running away together to get married themselves.

They discover that they are pregnant shortly after, but the happy news is short-lived when they find out that their baby has Type II Osteogenesis Imperfecta, a fatal condition that causes his bones to break in utero. They learn that their son, whom they named Samuel, would pass away a few hours after birth if he were carried to term. They decide to induce labor early, to keep Samuel from feeling any more pain, and say their goodbyes in a heartwrenching scene. The pain of Samuel’s death is too much for April and Jackson to bear, and rather than leaning on one another, April enlists in the army, and the pair spend nearly a year apart. They’re unable to reconnect with one another and ultimately decide to divorce.