Currently South Park is the smartest show on TV. They are truley not afraid to tackle any controversial current events (from stemcell research to homosexual equallity) they will make a show commenting on any and every major current event. The most refreshing thing about the show is it usually gives an opinion while on the middle ground, not usually taking any sides. Thye point out the stupidity in both ways of thinking when it comes to any given topic.
To anyone who says they lost interest in the show after the 3rd season, and hasn't watched it since. I highly suggest you watch some of the new episodes, the show is nothing like it used to be.
Futurama has that definate subtle edge of humour and emotion. Then Family Guy, which had some of the best jokes I'd ever seen. The Simpsons was great from Seasons 3-9, but since Matt's left the studio, it's been going down hill, such a shame. South Park repeat the same jokes too much and has had most of the humour wrenched out of it. There's only so many times you can laugh at a kid dying. So overall:
Futurama, Family Guy, Simpsons, South Park.