I'm not overly thrilled with any of the "cleanup" applications. Although they may remove files or registry entries that are technically unused, in most cases they're not causing issues either.

Yeah, a bunch of internet cache or temp files can eat up a lot of disk space, but the Windows built-in disk cleanup will take care of those if you don't want to do it manually. Apart from that, I wouldn't do anything unless there's a specific problem. There's always the risk of breaking something by deleting something that is used.

Whenever I get a new computer or upgrade Windows, I do a clean install at that point which gets rid of any accumulated clutter.