In no particular order.
1. Fallout 3 (All systems)
I don't think it beats ES: Oblivion, but it's certainly left a deep impression on me. But it's a really good RPG with a lot of content, interesting questlines and a lot of interesting locations to explore within the game.
2. Final Fantasy Tactics A2 (NDS)
Without a doubt, this was the best portable tactics game for me. With such a variety of classes and skills to play around with, beautiful maps and a good challenge (minus the annoying old law system of the previous), this is a tactics game I would keep going back to as long as the NDS exists.
3. Spore (PC)
The unique thing about this game is not that it is trying to teach anyone evolution or science, it is that you can create your own creature and direct what it will look like, how it will behave and its fate. It's fun to watch them grow and change. You can look at this game in many ways -- it is a creature design tool, it can be be a strategy game, it can be a game where you just want to make a most adorable creature, or a most destructive pet. Just don't take it seriously.
And that DRM the publishers insist on putting in, an unfortunate bitter bit in an otherwise good candy basket.
4. Condemned 2 (Xbox 360/PS3)
A really violent beat-em-up. If we have Streets of Rage today, it should be played like this. This horror survival adventure had some memorable moments, for me it was the bear chase and that ride on the barge that can induce sea-sickness in your living room.
5. Call of Duty 4: Modern Warfare (All systems)
There's very few FPS games based on modern day scenarios and this makes this a unique gaming experience. I've said it before here.