Credit: Scott Garfield/ABC via Getty Images Photo: Alex and Ava Kiss in Grey's Anatomy Season 4, Episode 5, "Haunt You Every Day"
3. Alex/Ava
In her heart-rending Season 3 finale speech, Ava begged Alex to give her a reason to stay. Although she succeeded in rekindling the flames, which glowed briefly when she returned the following season, Alex had to relegate her to the loony bin after she turned into a blubbering, suicidal mess. So much for what was once a sweet, earnest relationship.

2. Cristina/Burke
And we rest our case: The character of Burke was toast after Isaiah Washington got himself into hot water by using an anti-gay slur. Twice. Narratively, calling off the wedding was a logical development: Cristina was changing to suit Burke, and Burke realized it. But his departure was altogether too abrupt — Burke just exited stage right without any modicum of closure for his relationship with Cristina, which had lasted almost three entire seasons.

1. Alex/Izzie
Seriously, who would’ve guessed Alex and Izzie wouldn’t make it in the long run? Even amidst endless squabbles and breakups, the two always gravitated toward each other. Too bad Katherine Heigl decided to leave Grey's, resulting in a breakup for which there would be no make-up. When business decisions affect the narrative of a show, it gets ugly.

Credit: Michael Desmond/ABC via Getty Images Photo: Callie and Erica Operate in Grey's Anatomy Season 4, Episode 16, "Freedom"

5. Callie/Erica
Though Shonda Rhimes claimed to have broken up Callie and Erica over a lack of chemistry, online pundits have speculated that ABC wanted to "de-gay" the show. Sure, Callie and Arizona make a better couple, but Callie and Erica's short-lived romance deserved a smoother send-off. A disagreement over the Denny fiasco? Puh-lease.

4. Izzie/George
This time — twist! — we're talking 'bout a platonic relationship. Izzie and George were the best of friends before they screwed up... and well, you get where we're going with this one. Sure, he might have walked her down the aisle at her wedding, but after their ill-advised fling they were never the bosom buddies they once were.

Credit: Michael Desmond/ABC via Getty Images Photo: Alex and Izzie Talk in Grey's Anatomy Season 6, Episode 12, "I Like You So Much Better When You're Naked"
On Grey's, relationships seem to flatline as often as patients do. Breakups can be rational and graceful, but that's not always the case at Seattle Grace. Here are our picks for the 7 relationships that totally petered out.
7. Reed/Charles 
This one ended before it even began, thanks to Reed's standoffishness... and, you know, her being snappy with a man who turned out to be a mass murderer. Yikes. As he lay dying, Charles poignantly told Bailey to tell Reed about his feelings for her, not realizing she was already a goner. But hey, perhaps they're dating in the great Seattle Grace in the Sky.

6. Bailey/Ben
Bailey just can't catch a break. Now that the actor who plays Ben, Jason George, is playing a different character on Shonda Rhimes's new doctor show Off the Map, it seems we won't be seeing much more of Bailey’s anesthesiologist boy-toy. (Shonda, for the sake of continuity, no crossovers between Grey's and Off the Map! And no claiming that the two characters are twin brothers, either.)