The guide button doesn't do anything in my games on the PC, only on the xbox.
Start the game with the keyboard and mouse, go to the game options and look at the controller properties of course make sure the controller is plugged in before you start the game). You may have to tell it which controller you are using. Most of the games I play, I don't have to change anything. But Far Cry 2 and Avatar, I had to assign all the buttons manually (Avatar could read the controller, but the keymap sucked). Look at each function, like movement, then click it with the mouse and push the button on the controller that you want to assign it to. Go through all the controls this way. If this doesn't do anything, let me ask you something else...
If you have a copy of Halo 2 or Star Wars the Force Unleashed 2 for the PC... if you have the controller plugged in when starting the game, it will detect it and you don't need to do anything. Those are good games to test it on.
Take a look at this link. This is what I had to do to set it up with most of my games...http://www.wikihow.com/Use-Your-Xbox-360-Controller-for-Windows
Let me know if this takes care of it. If it is still unresponsive, could be a driver issue.