blackecho,
You have asked a question that I would like to know the answer to as well!
Presumably there are some sites somewhere with some authoratative articles about the merits, or otherwise, of Registry cleaning but, so far, I haven't found any.
I can give one example where cleaning was of practical help to me. We had a game which we decided to uninstall. Later, we tried to reinstall it but always failed. I used the very mild Registry cleaner that comes with Norton Cleansweep and the cleaner that formed part of jv16 PowerTools but they didn't help.
At some point I ran the sysinternals part of Spybot that checks for registry inconsistencies and, lo and behold, it found and removed a couple of old references to the game and we were able to reinstall.
It is possible that a cluttered Registry may cause problems when upgrading a program if the uninstall of the previous version was incomplete.
The dangers of messing up the Registry are obvious but, if you have a fresh backup available before each clean (rather than relying on the cleaners built in backup) you should be OK.
My HDD is only about one tenth of yours so I routinely use cleaner programs for Temp files etc. and now use RegSupreme for my registry. It always finds 400 plus 'empty useless keys' which appear to be created by my ISP, probably on boot up. Can you guess which ISP is so invasive?