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One thing to keep in mind, WPMU will be fully merged with WP 2.9. There will no longer be separate versions, so I've been waiting to try WPMU again until after that point (expected in a few weeks, since 2.9 is in late beta and almost ready for a release candidate).
I would use as few plugins as possible, sicne each one adds load and opens another up yet another bit of code that could have security issues.
So I would of course use Akismet and beyond that I would use as few as possible. Offer your users a few basic widgets for recent posts, categories, and that sort of thing.
During installation, you get a choice to configure for subdomains or subdirectories. I always use subdomains so I can't tell you about using subdirectories.
Make sure you have a wildcard entry for DNS. Not all shared hosting plans allow you to configure this yourself but most will allow you to put in a support ticket to activate it. I find this is the most common problem people have with installation.
Most but not all themes and plugins work with WPMU so I suggest you get used to the functionality without plugins and then add cautiously and make sure you haven't broken anything.
Donnacha's WP super cache plugin is great if you want almost static html like performance. Since WPMU is Donnacha's baby up to now, you can be sure his work will not break the functionality.
It really doesn't have to be a long long trip and the trip is worth it but the information unfortunately is hidden deep in documentation and forums. If the WP community at large embraces the code merge, then good things should be in store. If you are still stuck, PM me and i will try to help.