Have a unique key for each copy. When the game updates, check the key. If it's an invalid key (i.e. not one you created), or if that key's been used to update the game 100x before (i.e. lots of people are using the same copy/key), send an update that destroys the game. Otherwise, update normally.

This isn't foolproof, and your game will always be pirated, but this will impose an inconvenience to those who illegally obtain the game, and it just may deter them (a little). Don't spend too long worrying about it though, because someone will always crack the game. You'll also want to implement it carefully so you don't accidentally target a legitimate user (it's better to let 10 pirates slip by than to accidentally disable the game for 1 legitimate user).

*Disclaimer* I haven't actually tried this method, but it's one I've been wanting to try for ages.

Add online features that require you to have an account which has purchased the game. Theyll pirate it, but theyll probably want the online features too and buy it if its good.