Plants Versus Zombies is...genius. Somehow, it appeals to the casual time waster in me as well as the most obsessive, nuanced core gamer in me. I'm at well over 100 hours, and for 10 bucks, that's a pretty damn good deal.
Sanctum is probably my second, since it neutralized the less engaging aspects of most Tower Defense games by adding FPS elements. They managed to completely negate the downsides without interfering with the core tower mechanics, and even managed to integrate the 2 aspects in interesting ways.
Orcs Must Die and Defense Grid get props too.