I try to go through and figure out what some of that stuff goes to. The stuff that I figure out I just clean up the way I see fit. A good example from my stuff was easymoney. It is a banking app that makes backups of all data on a daily basis. I had files on there from last December when I originally bought my phone. They started to take up over 8Mb of space on the card and I was able to cut that down to less than 5kb.
The stuff that I don't know what it is I will copy over to my desktop or laptop and then delete. I know it sounds crazy, but if you copy the files off your card to the computer then you are covered for the most part. Then if something messes up you can always just restore the data you removed.
http://androidforums.com/all-things-root-eris/108911-apps2sd.html#post1154625
With mine, once I had it running EVERYTHING, but the OS moved over to my card. It is running very stable and I have about 143 MB of free space on the phone. The only stuff that stores on the phone is cache.