Monolingual is a good program to start with, removing unneeded languages from help files etc and the code you don't need from Universal Binaries.
Then you can get Onyx to run various scripts that Unix machines would normally run at 3am but since Macs are off at that time they don't normally run. Just go to the Automation tab and choose Execute and let it do its thing.
Appcleaner can be used to remove programs you don't need along with their associated files.