The O.C. - Ryan and Marissa
Do the constant make-ups and break-ups of Dan and Serena on Gossip Girl drive you insane? Well, Ryan and Marissa of The O.C. were the original Serena and Dan...and they made Dan's and Serena's problems seem like chopped liver. There was the resurfacing of Ryan's ex-girlfriend Theresa who became pregnant with his (possible) baby, Marissa's bout with lesbianism, the attempted rape of Marissa by Ryan's brother Trey and Marissa's eventual shooting of said brother (cue the Imogen Heap)...and if that wasn't enough to keep the two apart, there's that whole "Marissa's tragic death" thing.
Grey's Anatomy - Christina and Burke
It's too bad that all of the various issues between actor Isaiah Washington and the cast/producers of Grey's occurred (see here) or perhaps the Christina/Burke relationship would not have to appear on this failed list. The two were seemingly perfect for one another and the relationship survived its fair share of issues, including Christina's miscarriage a hospital scandal involving Christina's coverup of Burke's post-shooting hand troubles. However, the nail in the coffin for this relationship was Burke's running out on the two's wedding, packing up and leaving town, never to be seen or heard from again. Seasons later, Christina's character is still troubled by this relationship's failure.
Desperate Housewives - Susan and Mike
Bet you all didn't see this relationship's failure coming, did you? After all, we waited 3 seasons for Susan Mayer and Mike Delfino to finally end up happily ever after (and married)! However, at the end of the show's 4th season, the show takes a 5-year leap into the future and we are shown shocking footage of Susan coming home to a man that isn't Mike! Now in it's 5th season, Susan and Mike are divorced, their marriage not surviving a car accident that resulted in the death of a mother and her daughter. The two have both begun dating others, and continue to share custody of their son.
Friends (1994) - Rachel and Joey
We all knew that the coupling of Rachel and Joey on Friends was doomed before it even started; after all Ross and Rachel were the perfect couple. Some people disliked this story arc that developed in the later seasons of Friends, where Joey seemingly out of nowhere realized he was in love with Rachel. I think I was one of those people (at the time). However, thinking back, perhaps it wasn't entirely unrealistic that platonic friends of a friend clique might realize they have feelings for one another. It might not have worked out, but at least they gave it a shot!
The Big Bang Theory - Penny and Leonard
You might argue that this couple isn't failed so much as it remains in progress, but I'm kind of hoping that it remains in the "Fail" column. If you recall, the two have had a few almost moments - but things always go awry before anything serious develops. Personally, I think the show has been thriving without a Leonard/Penny romance - the two don't quite seem right for one another and the show works better with Penny merely as a friend to Leonard and a member of the gang. Not every sitcom couple has to end up together like Ross and Rachel!
Can you think of any other memorable failed couples? Share 'em!