I had an interesting discussion with a member of our group that stopped playing with us when we switched from 3.5 to 4e. Basically, I've come to recognize many of the complaints he had with the system right off the bat have sunk in for me - most predominantly the extreme "gaminess" of it all.
Even with the best intentions to stay "in-world" and not drift back to mechanics-land, 4e's rules are like a lens through which you view everything in your game in the game instead of a framework upon which you build and interact with the game world - and the lens keeps on bumping you in the face to remind you it's there.
That said, the issues I have with 3.x will keep me from running it again - namely the rapidly increasing power-disparity between PCs(op/non-op, spellcaster/non-spellcaster), the way high-level spells break my worlds without me realizing it because I don't feel like reading 500 rules spells just to figure out how they could break my campaign.
Also, 4e's (old) Character Builder spoiled our group heavily. I can make a couple paragon characters in the time it takes me to make a low-level 3.x character.
This is mostly, of course, is running games - I'll play anything once (and keep playing if the DM is good). For running games:
*Savage Worlds and the like are too rules-lite
*4e is too rules-first
*3.x is too "rules-wide"
*Dark Heresy, Star Wars, and Exalted are too rooted in their own settings to be easily extracted for other settings
*GURPs is too... GURPs. One of the few systems I've played where rolling the dice isn't fun for some reason.
I'm working on my own game system mostly out of lack of the system I seem to be looking for...
