I don't know how difficult this would be, but I sure would like to see an option to do a single site installation.  This would allow images to be placed in "/images", instead of "/data/sites/1/images", for example.  I know my users would find that a lot easier to work with.  Given the difficulties with backing up and restoring individual sites within a multi-site install, I can't imagine a situation where I would use a multi-site install.  I'm sure others use them, but having an option would be nice.