Well, if you see entries for programs or files that you know you've uninstalled/deleted, then those are safe to delete.
Usually, entries referring to Temp folders are safe to erase.
Useless file extensions are usually safe to delete, but they seem to come back, so . . .
In any case, let RegCleaner make backups so if something gets funky, you can restore the entries. (Hint: do your deletions in stages so the backups will also be in stages. ex. delete your Useless file extensions in one stage, your invalid files/paths in another, etc.)
BTW - so far, since I've had Vista, RegCleaning hasn't made one bit of difference to the way my system runs. Probably because my OS condition is sort of new and really doesn't need a cleanup yet. But if you've let things go, and have lots of junk in your registry, it may have a bigger impact.