The debate can continue endlessly and it really is just a matter of opinion. I want to hear yours!
The Simpsons- Since the end of 1989, the Simpsons have been a staple on television. Their popularity peeked in the 90's however, this cartoon family has been going strong since day one. The envy of every other cartoon, the Simpsons have been cutting edge and have covered a wide range of topics and is the longest running American sitcom. This is the pioneer and the one that paved the way for the others.
South Park- Trey Parker and Matt Stone created this monster and aired it on Comedy Central in '97. Not afraid to shy away from any topic, South Park has reinvented itself over the years producing new episodes that are relevant to current affairs in the world. They often parody famous celebrities and are constantly flirting with the idea of going over the top. While they don't have as much pedigree as the Simpsons, they are clearly heavy hitters when it comes to the debate.
Family Guy- Seth Green's Family Guy has a Simpsons feel but is a bit more brute than that. With Brian, a sarcastic talking dog, Family Guy tries to bring in its audience with flashbacks and memories that create the humor. It's plot usually is something to be desired but the characters recalling previous events always seem to bring in a pop culture reference that many can relate to and laugh at.
Honorable Mentions/Others worth noting:
Futurama
Rick and Morty
Archer
Bevis and Butthead