Akismet
Akismet - Anti Comment Spam - it works and its simple.
This plugin does just what it says, nothing more, nothing less. Its a simple install that requires a key thats free to get and you can use the key on more than one site so its painless to setup and use considering the gain.
This plugin has been tested with WPMU and no issues have been found, users will need to register their own key, I have not found a way to make it automatically work for all users, but really - its not that big of a deal!