The PerlMonks codebase already does something like this using path info, although the index.pl is not optional: http://www.perlmonks.org/index.pl/jacques.

In theory, it should be easy to add an ErrorDocument direective to the PerlMonks httpd.conf that handles all 404 errors by sending them to index.pl, which would allow node names to be used as addresses, without writing the "index.pl/".

Update: You can also use node IDs the same way: http://www.perlmonks.org/index.pl/223311