Mass Effect 2, obviously.
I've never been so pulled in by a game franchise before. We're all on the edge of our seats waiting to complete our personal stories with the trilogy finale.
This has spanned years, mind you. No other game, that I can personally remember, has been so breathtaking. They really pushed the envelope with ME2. The only people that didn't like Mass Effect 2 (or 1) that *I* have seen, are people who say.. "There is too much talking." It's an epic space-opera folks.
Red Dead Redemption would be my close second. However, it didn't really innovate in many departments, other than stunning atmosphere... aand I'm not exactly still on the edge of my seat from anything in Red Dead Redemption.