I remember playing this years ago on Wild Tangent, long before I switched to Steam, and it's still just as fun as it was then, maybe even more now that I know what to expect.
Defense Grid is among the best you'll find in the Tower Defense genre, and rightfully so. This game has a tantalizing blend of simplicity, planning, general enjoyment and even graphics. One of the largest pluses to Defense Grid is that it allows you to progressively shape the path your alien foe take. You can also set up "kill zones," places where you concentrate your best towers and where most of the killing happens, hence the name.
Another huge twist in Defense Grid is that your enemies have to go to a central hub to take a power core, essentially hitpoints. If you kill an alien who is holding a core, the core will progressively float back to the hub unless another alien grabs it. This makes strategy much deeper than "don't let them get to the end."
Your AI friend who is booted up in the prologue is your constant companion, giving you tips and commenting on how you're doing or what's going on (this has saved my ♥♥♥ many times when I was focused on improving outer towers and he told me that aliens had their grabby little hands on a core, and they wouldn't left the map with it if my AI friend hadn't told me in time).
Another great, possibly unintentional twist is that your AI friend has a British accent. This somehow makes his warnings more spoken and his cheers more cheerful, plus it sounds so classy when he says "bloody hell."
Some maps also have multiple levels to them, where aliens have to go up in a spiral to get to your cores. This opens up a huge amount of possibilities for towers that help cover multiple levels.
Overall, I'd have to say Defense Grid is one of the best if not the best game you'll find in the Tower Defense genre. Your Tower Defense collection can't be complete without this game. Definately get this if you're into Tower Defense.