I just finished Andrew Nacin's "Tylenol" post. Off the top of my head, I think this idea could make Multisite easier to configure.
Let's say you have a potential super_admin. You're offering him/her many, many choices, in terms of possible structures. Overwhelming? As far as who gets access to what options on this domain but not on that network--on this site but not that domain.
What I'm suggesting is like a "choose your own adventure" story. Instead of "Turn to page 86 to slay the dragon. Page 19 to run away." you could present a few attractive diagrams of typical network arrangements. One network diagram might show one site per domain. Another network diagram might have multiple sites per domain. From less complicated to more complicated.
Once you choose the diagram/structure you want, WordPress takes you out of "everything is possible" mode. From that point forward you hide all non-relevant Multisite admin options.
You could set up diagram choices for typical user/permission hierarchies too.
It's just an idea.
Granted, I've never used MU or Multisite myself--maybe the interface is already really easy to understand.