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The Most Devastating ‘Grey’s Anatomy’ Breakups of All Time, Including Multiple Meredith Splits

Grab a box of tissues and prepare for sappy voiceovers. Meredith Grey, Alex Karev, Cristina Yang and more Grey’s Anatomy characters — past and present — have been through the romantic ringer since the show began in March 2005.

Related: Every Star Who’s Left ‘Grey’s Anatomy’: Where Are They Now?

The ABC drama’s leading lady, Meredith (Ellen Pompeo), has had it particularly rough, given her on-again, off-again relationship with Derek Shepherd (Patrick Dempsey) and his eventual tragic death.

In fact, several Grey’s Anatomy splits stemmed from the actors’ decisions to depart the series. “In order for a one-hour drama to continue, there has to be big upheavals,” Pompeo told Us Weekly in August 2015. “Every time we’ve lost a major character — we’ve had such amazing characters on the show and every time we’ve lost one, it’s been devastating and sad. You think, ‘How can the show go on?’ But that’s how the writers find inspiration. So the loss of the big characters is exactly how the show does go on.”

The Most Devastating Greys Anatomy Breakups of All Time
Ellen Pompeo as Dr. Meredith Grey and Patrick Dempsey as Dr. Derek Shepherd on ABC’s “Grey’s Anatomy”. Bob D’Amico/ABC

Related: TV Couples That Need to Get Together in 2020

Though Meredith moved on, which resulted in another sad breakup for the doctor, the actress believes her character does not necessarily need a leading man in her life. “Annalise Keating carries [How to Get Away With Murder], Olivia Pope carries [Scandal]. But somehow, Meredith Grey needs someone,” Pompeo noted to Entertainment Weekly in September 2015. “Why can’t I just be the lead of the show the way Annalise and Olivia can? Why can’t I be on that poster by myself?”

Alex (Justin Chambers) had a similar experience when Izzie Stevens (Katherine Heigl) left him single in season 6. Their split was caused by the Suits alum’s exit from the show.

Related: Alex Karev and Izzie Stevens: Revisit Their Relationship Timeline

But what goes around comes around in Seattle, apparently. When Chambers chose to leave the series in season 16, he abruptly called it quits with wife Jo Wilson (Camilla Luddington). He instead rekindled his romance with Izzie, given that she was raising their twins elsewhere.

There is always hope that fans’ favorite couples — perhaps Jo and Alex? — will be endgame. “The reason [Alex] wasn’t killed off is because Shonda Rhimes is leaving the door open for a return, in any capacity, if he wants to come back,” a source told Us exclusively in March 2020.

Watch the video above to relive the most gut-wrenching breakups in Grey’s Anatomy history.

Grey’s Anatomy airs on ABC Thursdays at 9 p.m. ET.

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