My D&D specific experience is relatively limited, but I played Shadowrun for many years with some friends in high school and college, which I think qualifies me at least to give some general advice about running a game.
My first thought is to know your players. Are they min-maxers? Power gamers? Antagonistic towards each other or to the world in general? Carebears? Hardcore roleplayers? We often had problems because the guy who was our game master was a strong roleplayer, while the rest of us were more of the min-max or power variety. We wanted combat, lots of it and limited consequences for blowing up bars. He wanted us to seduce CEOs or sweet-talk our way tense situations. You can see why this would be a problem.
Secondly, you definitely need to know your rule set and there's just no getting around that, particularly if your players are also sticklers for it. Nothing throws a gaming session like having the GM insist something works one way and a player insisting it works another and then having to dig through the books and having one person feel vindicated and the other shit on. I imagine you're probably more mature than a bunch of high schoolers, but it still disrupts the flow.
Also along those lines is figuring out how to keep the players on your campaign while still giving them some room to move around. No matter what you want them to do, they're probably going to find ways to get themselves into trouble doing something else along the way, and the more natural that feels, the happier everyone is going to be about continuing along the big picture.
As a final recommendation, you might find some inspiration, or at least some humor, by reading either 8-Bit Theater (
http://www.nuklearpower.com/latest.php) or Order of the Stick (
http://www.giantitp.com/comics/oots.html). If you have time, read both. It's good times either way.