I just spent a few hours going through all this over the weekend.
Fortunately I have 2 internal drives, so this makes things much easier.
First of all, I create a desktop STORAGE folder for all the stuff I download or don't have the time to put away properly.
Once the contents reach the size of a CD, it's time to either put stuff away, burn it to CD or trash it.
Hopefully you have Toast 7
I make a habit of creating a folder for each Application installer .dmg or .pkg
I also drop in a Text Edit document with all my authorization serial numbers, version number etc for each corresponding installer so they
are always together. You can also throw in a copy of any plugins or updates
so everything is together.
If you search your HD for "packages" you should find a folder containing
all of your OSX update and Security update .pkg installers.
I burn all of these to CD in the event of a major crash, so that I can restore my system up to current specs fairly quickly.
Burn a copy of your latest USER/LIBRARY/PREFERENCES folder.
Especially your addressbook.plist and your bookmarks.plist.
You can burn copies of everything in your HOME folder, but many people
forget to save their address book contact list and their bookmarks.
I still wish that MAIL included an easy option to print the address book, just in case.
Documents!
Make damn sure you burn a copy of those tax return pdf's, reports, databases, passwords, song libraries, birthday and anniversary list, bosses phone number etc.
Photos and iTunes library.
Carbon Copy Cloner is an excellent way to back up your entire system, but it also helps to know what many people forget.
There's also BackUpUserprefs available at Version tracker.
I also keep Data Rescue II and Disk Warrior loaded and ready to roll
on my storage drive.
That's all I can think of at the moment.