It would be nice if core files, plugins, themes and uploads respectively would be kept separate of one another - both as locations and as objects.
That would make it much easier to move servers or switch between versions in case anything goes wrong.
Several websites could share a single install. It should also make it possible to specify different log-in paths - on subdomains or even different domains.
It would probably take some amount of symlinking and hooking into the existing code to preserve backwards compatibility.
example of directory structure:
*each with their own config.php etc.