I have narrow interests when it comes to video games and my perspective is therefore limited so take this for what its worth:
Halo - Defined the fps and multiplayer with a great story to boot.
CoD4: MW - Re-defined the fps and multiplayer.
Mass Effect - Immersive rpg with great character customization and exploration of the galaxy and its civilizations. Basically its what a Star Trek game should be.
Assassin's Creed 2 - The first one was repetitive but the second one gave Ubisoft their own CoD. I also though it was a pretty original IP.