I'm on a Mass Effect bender at the moment so it's somewhat tempting to say Mass Effect 1 or 2 (I like aspects of both of them, I honestly can't decide which I prefer).
But no, I'm going to say that the game I consider to be the best ever (so far) is Beyond Good & Evil. It has a sublime balance of compelling story, interesting, well developed characters, excellent level and creature design, gameplay that is fun and above all works, and it is neither too short nor too long. A recipe for a perfect game, if you ask me.
Honourable mentions: Mass Effect 1 and 2, Chrono Trigger, Lufia 2, Heroes of Might and Magic 3, Master of Orion 2, Banjo Tooie, Phoenix Wright: Trials & Tribulations, Metroid Prime, Jet Force Gemini, Paper Mario & The Thousand Year Door, Portal, Shin Megami Tensei: Devil Survivor, Super Street Fighter 2, Assassin's Creed II... I could keep going. All of these are superb games, but I still feel Beyond Good & Evil ticks just about every conceivable box for what makes a game great.