I had one problem with WPMU that required me to hack core. I glanced through the Beta code for WP3, and it looks like I'll still have the same problem, but I haven't looked very much in detail, and was wondering if a better way existed for WP3.
My problem was that in WPMU, it required the site not to be on a http://www.example.com url. This requirement makes absolutely no sense on a subdirectory install (which is what I maintain). Commenting out two lines of wpmu-settings.php fixed it, though.
Some variation on these two lines is found in about four files of the WP3-beta code.
I'd really like to be able to cut out the core hacking (fixing it after every upgrade is annoying), but I'm not sure if I'll be able to or not.