Two of my less well known favourites are Larry Gonick, the overeducated cartoonist, and Dan O'Neil, who both published in Whole Earth. When that rag dropped R. Crumb in favour of Jim Woodring, I sensed that their days were numbered. Crumb had done a simple page of small panels of a crossroads in America, showing it about every decade, from a simple shack on a trail, to a railway flanking the road, and on through the depression, etc. Trees grow and die, the shack becomes a house, and then a restaurant, and eventually a shack for a used car lot. It is one of the most thought-provoking things I've seen.
Another unsung genius is Lynda J. Barry, who also does some standup. Her plot lines are bizarre and fun, such as an ad that switches the target audience half way through, but her drawing is very marginal. Harvey Pekar thought his was just not acceptable, and got his observations of the human condition illuminated by R. Crumb and many other famous artists.
On the popular list are Gary Trudeau, whose punchlines can still make me chuckle just from memory, and Gary Larson. His Far Side would have vanished without a trace if not for a single sales call getting lucky. Calvin and Hobbes are another handy way to laugh at human quirks, instead of getting snared ourselves.