See http://kb.mozillazine.org/Preferences_not_saved

Start Firefox in Diagnose Firefox issues using Troubleshoot Mode to check if one of your add-ons is causing your problem (switch to the DEFAULT theme: Tools > Add-ons > Themes).

See Troubleshoot extensions, themes and hardware acceleration issues to solve common Firefox problems and Troubleshoot issues with plugins like Flash or Java to fix common Firefox problems

I've installed the beta version 4, so I believe I have two firefoxes sort of sharing a profile. I followed the steps and still, about:config isn't keeping setting changes.

- I tried the 'reset all' function in Firefox Safe Mode - I backed up settings, deleted my user prefs file, restarted and forced a new user prefs file.

Still no joy. Probably my final option is the nuclear one and I'm holding off until FF4 goes gold to do that.

Did you check for the presence of a file user.js in the Firefox Profile Folder ?

Help > Troubleshooting Information > Profile Directory: Open Containing Folder

Be careful with using a Firefox 4 beta version in your Firefox3 profile. Such versions may update files to a newer version that may cause problems now or if you start using Firefox 4 with that profile at a later time (e.g. when Fx 4 gets released).

See also http://kb.mozillazine.org/Testing_pre-release_versions