I've been giving talks and demos recently of Drupal. There is a best practices guide on the Drupal website but it does not cover some of the things I'd like to figure out.
I've come up with a very nice setup that uses DNS wildcards to send all traffic for a domain (and any sub-domain) to a given server. Apache is then configured to pass it all to Drupal. The enhanced sites functionality in 4.6 is great. Almost. It allows a great deal of flexibility, but there is a database sync issue. I want to give a blank database to each person who signs up for a site. But, I want to give more than the skeleton modules. This isn't too bad to setup one "skeleton" database and copy it each time a new request is made.
Until it comes to updates. Now I've got 100 databases with content in them and an upgrade comes along. Now it is time to upgrade all the databases. Or a new module comes out and we want to use it. So either each database has to be updated or the installation has to be frozen for long periods of time.
Another area I'm working on, in part because of the lousy satellite internet, is synching multiple Drupal installations. For speed and sanity reasons I want to do the editing of templates and most content locally and then have it sync to the central installation(s) of Drupal. No sleep for the weary!