As a rule I have them on while only once over a lengthy period of time use one for cleanup only. But if I know one program is gone I will go right into the registry to locate and remove anything left behind before buying Regcure or Registry Mechanic by a long shot.
One of the drawbacks with RegCleaner while never seeing any problems with the registry cleanup option found in tools is that it opens right up to a main window displaying the main keys for all non MS programs installed. The only time that is good is when a new unknown bug(like going to tvguide.com and seeing a tvguide icon appear on the IE address bar) I'll look at the new entry seen right at the top to see a strange name and check it off and press the remove button.
(Nothing like seeing "swearware" as a new item there and knowing who put it there! :mad: Grrr...)