I was thinking more along the lines of outside of the average reader's mainstream, but something that would be familiar to a true comic geek. So, The Watchmen, for example, used to be a comic-geek's favorite, but now, everyone has read it - it is mainstream.
I really like anything that Bill Willingham comes up with, but I think that the Fables comics are gaining in popularity. Of course, Gaiman is God, but most people have come to the Sandman by way of his other mainstream projects (like Coraline, Stardust, etc).
Well, then I mostly stick by my list

- some of it is a little obscure and mostly found in anthologies like MOME, but all still really good solid stuff.
Fables is great - plus you get those amazing James Jean covers.
Garth Ennis' Crossed is good - brutal and will give you hella nightmares, but it's well written and engrossing if you like apocalyptic stuff.
Garth Ennis' The Boys was good but I really hate it now - I only read the first half dozen issues before I felt it went off the rails and became kind of just over the top disgusting for no real purpose.
Warren Ellis' No Hero is pretty great stuff - not widely read for some reason but good.
Robert Kirkman's The Walking Dead is the only book I've picked up consistently for years and although it's pretty popular, it's still technically not "mainstream" Unfortunately, it's fallen off in quality over the last year. I still pick it up, but it's definitely not the book it once was.
I think books that are great like Watchmen but less widely read would include Alan Moore's Top 10 (there are two trade volumes I believe); Warren Ellis' Planetary (the last issue of which is coming out soon); Preacher and Y The Last Man (but maybe those are at the Watchmen level at this point?)...
You've made me want to just go read awesome comics for days!
