A particular enemy who doesn't want the main characters to be happy.
Society, man. People in general just won't let my characters live.
A magical curse, a prophecy, or another fantasy-based element.
A illness afflicting one or more of the main characters.
Me. I tend to shake things up whenever I get bored.
My characters are their own worst enemies and cause most of their own problems.
The environment my characters live in is the source of their unhappiness.
The game itself. Crashes and lags are ruining my characters' lives. And mine.
A large group of enemies like zombies, aliens, or an entire government.
Something else not listed here (I'll write it in the comments).
I don't want to vote, I just want to see the results.