First thing, use vlite to slim down the installation to only the parts that you need. (But I think you are past this stage.)
Then get service packs (a big help in reducing the annoyances- particularly with wifi, sleep and general speed) and updates, install your known essential programs, get rid of trial programs and the like, maybe use the blackviper reference site to stop some services that you know you don't need (be careful!) Use Windows_Tweaker to make it just how you like it- most of these can be done through Vista, but telling it to "not restart after updates" for instance is easiest with this tool. Use Key Tweak to change an alt gr or insert key to something useful. If you trust yourself, get rid of the intrusive User Account Control, but you should work as a non-admin user anyway.
Make a disk image with driveimage-xml or other. You can then backup from this rather than a full reinstall. Useful as you might find yourself experimenting with programs and settings a lot.
Set up the quick launch bar with well used programs, and launch them using the win + num shortcuts.
Use lifehacker or other trusted sites to search "vista tweaks" or "speed up vista" and things like that.
All this applies to any Windows OS really. As for Vista, using the search facility is by far the easiest way to get around the system.