Periodically, and for no apparent reason, the left mouse button would quit working on my USB Mighty Mouse. Unplug and plug, still inoperative. So I tried another non-Apple mouse, still inoperative. When this happens, the right mouse button works and could activate menus, but I couldn't click on things (I used a right-click and the arrow keys as a workaround to activate menu items). If I restarted the machine, the left mouse button would work for a while. Eventually, though, the problem began to occur immediately on boot. AppleCare suggested things like resetting the PMU, PRAM, etc., but to no avail. Their next solution, on this relatively new and unadulterated Mac, was to reinstall the system software -- not something I was anxious to do, nor did it make sense on this new Mac!
After some digging, I found the solution. It turns out that the Bluetooth mouse and keyboard were enabled, and a nearby Bluetooth mouse had a near-dead battery - I didn't even know there was a Bluetooth mouse nearby. So I disabled Bluetooth while the problem was happening (i.e. not after a restart), and the problem disappeared -- my left mouse button works again. I've had this same problem when I bring my computer to work -- perhaps someone else's Bluetooth device (maybe even a phone?) has been interfering.
In short ... check if Bluetooth is active and look for any nearby devices if you're having odd troubles with a wired mouse.
Mac OS X Hints