Do you play PS more as a sandbox style campaign, or more as a plot-centered campaign?
I've wanted to run a PS campaign for a while, and it recently occurred to me that a great way to showcase PS's awesome scope is to let the players decide where they want to visit. Of course, that awesome scope is what makes PS probably the most burdensome setting to run as a sandbox. Anyway, I'm just curious.
I'd think that to run a sandbox styled PS game, you (as DM) would have to be really familiar with the PS universe. Maybe not so far as NPCs go (the Planes are a big place, so you're not going to run into celebrities every time you visit a place), but certainly in terms of the character, look and feel of each place that gets visited.
Likewise, the players themselves would have to have slightly more than a passing familiarity with the setting, otherwise they'd risk getting bogged down due to the sheer scale.
If you had both of those things going for you, there would be no reason to jump in and get to the meat of the setting: heavy amounts of philosophy and adventure set against a fantastic background. Where the overall populace is jaded and cynical, but the true believers are the movers and shakers.