The only time the show really pisses me off is when it fucks up its own continuity, tenuous though it may be.
I was very annoyed by the lame reveal that Cartman's father was Mr. Tenorman. Not only is it not that funny, but it also ruins the hysterical "Cartman's Mom is a Dirty Slut/Cartman's Mom is Still a Dirty Slut" episodes from Seasons 1 and 2.
And I also hated the Mysterion garbage, which I think takes a lot of fun out of Kenny's deaths in the early season.
Basically, I don't like the way Trey and Matt treat the early seasons. They always seem embarrassed by them, and now it's like they're going out of their way to mess with them.