I see a lot of suggestions stating to do the Virus &/or Spyware scans in "Safe Mode". Is that a good idea? When should you scan in normal mode or safe mode? Whats the difference?

I run my AV/Spyware scans in Safe Mode, when these programs are having trouble getting rid of a particular file, or I suspect that my computer might be infected.
Otherwise, I do my regular scanning in Normal Mode.

Definition of Safe Mode

The Windows operating system protects files when they are being accessed by an application or a program. Malware writers create programs that can insert itself and hide in these protected areas when the files are being used. Using Safe Mode reduces the number of modules requesting files to only the essentials to make your computer functional. This in turn reduces the number of hiding places for malware, making it easier to find and delete the offending files. Using anti-malware tools, Scandisk, Chkdsk, Defrag, & Disk Cleanup in Safe Mode also speeds up the scanning process.