Jan and Wayne's marriage slowly falls apart as the series goes along due to Jan's implied affair with Steve Brule.
Steve himself is an extremely awkward manchild.
Casey is obviously a parody of severely mentally challenged kids who have amazing talents.
Tim and Eric themselves. Tim is starved for attention and even his own parents favor Eric over him, and Tim pushes Eric down the stairs in the 50 anniversary reunion episode. By the Chrimbus Special, it's apparent that Tim's hate for his partner and self-esteem issues are festering and festering hard.
Distant Finale: They did this one prematurely, with a fake 50th anniversary episode.
Eye Scream: In "Crows", Tim and Eric get their eyes pecked out by crows.
Flanderization: Casey seems to grow more sickly and physically repulsive as the series progresses, compare his first appearance, where he's somewhat composed and only devolves into sputtering and gagging when the song begins to skip, and one of his later appearances, where he's visibly sweating and rash ridden and far more prone to aggressive outbursts of sneezing, violent gagging, and occasionally vomiting.
Snap Back: Tim has died at least five times. In "Resurrection", David Liebe Hart even comments about how death is not a big deal for Tim. However, things don't always snap back at the end of an episode. Casey remained dead until being reanimated by his brother, but Steve Mahanahan, who died in the same explosion, came back to life with no explanation.
Too Much Information: Many, many skits derive their humor from this, particularly anytime when Will Grello (played by Will Forte) reveals disturbed events from his childhood.
Toilet Humor: A pair of pants that allow the wearer to avoid the bother of using the toilet. Another sketch had an invention that allowed the male user to poop using a urinal while standing the entire time. Yet another product was an adapter to use a urinal to take a shower.
Tim and Eric have stated their intention to have every season opener feature a diarrhea related Cinco product.