I'm considering switching my computing situation around and have a question. If I have two computers, each with a copy of PhpED installed, will I encounter any difficulties if I store all my project information on an external hard drive and move it between the computers? I know the IDE stores a lot of settings in its own folder and in the Windows registry, and I'm wondering if any of that will throw things off.

I'm currently working just like the way you describe, using a USB key to share development folders between my desktop and my laptop.
You just have to create a "USB project" on each computer, maybe with different drive letters (my key is "F:" on my desktop and "H:" on my laptop).

With a fast USB2 key the response time is very quick when debugging, also with heavy class files.
I feel no difference with debugging on the hard-drive.

For the rest I have no problem.
But as usual be sure to take regular back-up of your USB folders on your local drive, just in case of ...

Have fun

Great, thanks!