Some thoughts:
First, familiarity can't be beat. You need to study the rules to know whay they can do; this is why I keep the PHB by my PC so I can read while it's loading whatever it's loading. More importantly, familiarity with established settings can be very useful; it does, however, require a little more prep time to convert the Belgariad into d20 even if your players can recite half the Rivan Codex and need no introduction to the world. Is it worth it? I don't know; I run a homebrew setting. (Actually, because it's medieval Europe, I still have that familiarity advantage as well as the single biggest collection of sourcebooks for any campaign setting ever.)
Second, flexibility is an illusion. If the PCs know what the DM has prepared, they know too much. Prepare what you want to use and nothing more; the PCs will encounter what you want them to. Why roll dice to find wandering monsters? Take a little time and design a half dozen wandering packs, and throw them at the party in sequence. You can roll them independantly, but you don't have to roll them during a game session. (Again, this requires prep but smooths game time.)
Similarly: Design adventures that can be plugged into any circumstance. Some of them can be obvious side-tracks. However, side-tracks aren't accidents; they're planned carefully. I did this in my campaign; the PCs still think it was a teleport malfunction that landed them in this dungeon full of traps and intricate history, wheras I actually set up a whole system of magical defences with the side effect of plunging them into the Tomb Of Dread. (My name; it's unofficial but describes it pretty well.)
I prepped the dungeon ahead of time and was amazed when the PCs took two sessions to get to it; they travelled to Budapest, educated a dryad, teleported a wagon down the Danube, ran from a dragon, fought gnolls, made a diplomatic faux pas with an elvish Duke and dealt with orcish merchants before reaching the dungeon in a desert somewhere. I had to do all that on the fly - a side track from the side track. Point is, the PCs went exactly where I wanted them to go no matter what they did. THEY don't know what's around every corner; YOU do, the DM. So don't plan every corner; plan one corner, and make it location-nonspecific so the PCs find it around the first corner they investigate. If all goes according to plan, they won't ever go back to find those other corners.
Third, creation is its own reward. I can think of little that's more fun than sitting down and writing/planning/drawing something cool, all on my lonesome. Although maybe that's just me. I've done fifty pages of races for another homebrew campaign so far, and I haven't even considered inviting people to play in it... they're MY toys! Mine! Precious!
Ahem.
So yeah, prep is important... but so is general knowledge and preparing only what you need.