It definitely depends on how you use the files and how many files you have. My basic folder structure is:
0. Inbox
1. Pending
2. Current Projects
3. Reference
I have the same folder structure on my work computer and my two home computers.
Inbox takes anything that I don't know what to do with - interesting PDFs, email attachments that I haven't decided whether to action, etc. I've set up Firefox to direct all downloads into my Inbox rather than my desktop. In theory this folder gets cleaned once a week as part of my weekly review.
Pending takes anything that is waiting on other people or is a someday/maybe project. Normally this is pretty empty.
Current Projects take files that I use often and that are related to, well, current projects.
Reference is easily the largest because my workload involves very long activity cycles (I edit an academic journal and am a researcher). At work, I have to keep material from the past several years, and files on all of our books that are currently in print. At home, I have loads of PDF articles (not tens of thousands, but thousands) and illustrations and bits of information 'just in case'.
Both Current Projects and Reference are split into subfolders. I try not to use more than 3 levels of folders (so an example would be Reference - Book Title - Reviews) if at all possible.
In order to completely trust my system, I use Copernic desktop search which is free and easy to use. That way, if I have put a file into the wrong folder I can still find it.
The one thing that I'm trying to get better at is including dates in the file titles. I often work on the same file at home and work and rather than trying to make sure all computers and my flash drive have the same version of the file, I'm now getting into the habit of dating sucessive versions so that I don't accidentally delete the current version. I can always delete the older versions once the file is complete!
