I really like Plants VS Zombies and Defense Grid, but I tried to play a few out of the millions of free online tower defense games and I find them pretty boring in comparison. Plants VS Zombies and Defense Grid are both designed brilliantly. It starts out with a basic objective to defend yourself from a wave of enemies, but it builds and builds on that basic goals with new weapons, new enemies, and new terrain. The goal is the same, but the way you reach it changes with each new element added in a level. By the later stages, you are pulling off some really complex strategy. What makes these games fun is that you are learning complex strategy the farther you get and the game designers have designed the game to fit your expected learning curve.
What makes this genre great, is also its potential downfall though. Once you have played a few tower defense games, new ones don't seem to add much other than a new setting and once you are familiar with the kinds of winning strategies you need, having to go through another designer created learning curve is kind of annoying. Maybe I'm wrong, but I don't think the genre can sustain itself largely because Plants VS Zombies and Defense Grid are so good. Who knows though.
Sanctum has an interesting take on the genre that combines tower defense with first person shooting. I suppose a creative designer can make anything work.