Can you post some of the typical errors you get? Otherwise, it is difficult to guess what the problems might be.

I know Mac isn't designed to use su, but I did set up a password for root and there are times I use su instead of sudo. After seeing your question, I tried it from my account with sudo and it referenced using the config files from my home directory, rather than root's home directory. It went through the configuration process and then I tried installing Mac::Applescript and it installed without any problem. (This was a module I could not install before.)

So it seems that running it under su yields a totally different behavior. But why, if the .cpan directory was deleted in /var/root, does it not try to reconfigure when run by root, as opposed to under my account with sudo?

I can go back to using su and post some examples of it not working if that helps, but this seems to be what fixes it.