tis a tough question indeed. i would say mass effect, but that was a trilogy from the start. would say bioshock, but that has a sequel and another on the way.
would say deus ex, but that's the second game in the series (and one hell of a prequel to the original. cant wait to see where they go but i digress)
also loved Star wars: empire at war, but they made another.
Terraria is fun, but not the best by any means. nor is minecraft (but both are really damn fun)
I almost forgot about World in Conflict, but that was one hell of a game. the gameplay i remember was great, and i also remember enjoying the story a good bit (which is a rarity for me and strategy games, as i usually don't even pay attention)
but for sheer stupid fun, Vanqush and Bulletstorm. my god i played barely any vanquish (as my brother enjoyed it much more than i and so played it more), but holy fucking shit it was awesome. Bulletstorm... well draging a guy by the testicles into his friends to then cause him to explode killing them all, all with a sniper round from 200 meters, just fantastic.
in short, i cant decide. but among the fantastic sequels of this generation (fallout, halo, gears, deus ex, left 4 dead and so on and so on), we have had many good new IPs, which is a damn good thing to know.