I tend to take a simplistic (but not non-savvy friendly) approach:
I use CCLeaner, Revo Uninstaller, Defraggler now and then, and the Windows Services Control to keep my PC streamlined.
I use CCLeaner for temp files, browser cache, etc - also for simple AutoRun disabling (I don't like MSConfig personally).
Revo Uninstaller is the only program I uninstall with, It searches for leftover files and registry entries after the program's uninstall completes, and allows you to remove them.
Defraggler is a very good defragging program, never had issues with it.
Now, for the nitty gritty I use the Windows Service Control panel applet; There are some programs that install themselves as services (that you don't need) and cannot be turned off via MSConfig or another auto-run program disabler.
I also found a spreadsheet on Tech Republic that shows a list of Vista Services that are safe to disable (depending on your machine's usage/configuration) that helps get rid of the general Vista garbage I don't need (if you use XP then there are resources out there to tell you what you can safely disable as well).