Keep it Gay
Roleplaying games do very well when they can be flexible. Humor is good for this because, hey, it is just a game after all. The goal isn't to gain experience, achieve a vicarious sense of accomplishment, or even to add numbers to more numbers to have the best numbers. No, the goal is to spend time with friends and have fun. Yes, a serious campaign of seriousness is a good idea, but it takes not only a prepared storyteller, but a cooperative set of players as well. I think because humor is the basis of a flexible campaign and because everyone is there to have fun, poking fun at the incongruities and laughing at the flaws are something that everyone's used to. It's like quoting Family Guy: it's an easy, safe way to get a laugh, but you have to get past it to get to that next level. Unlike Family Guy, getting into a serious campaign requires the dedication of an entire group, but promises greater rewards. On the part of the players, it requires a level of interaction greater than ignoring incongruities, but less than outright lampooning them. For the storyteller it requires distinct, consistent characters, easily readable tone, clearly explained plot points and devices, enough events to compel players to return, and a story sound enough to hold up to the scrutiny of characters (not players, necessarily).
Ultimately, no matter how much you love your Non-Player Characters, the story is about your Player Characters. NPCs are great, but focusing on them is hard to do. If the spotlight is on the NPCs for too long, players might just feel like they're bit players in your grand design (and even if they are, they shouldn't be aware of that). PCs should be performing pivotal actions and making big decisions. It's not that NPCs shouldn't be important, it's that no matter how important we are, the actions of the characters are both center stage and of vital importance. If Divis Mal and Caestus Pax are duking it out in the skies above the players, make it the background for the players' actions. The ground trembles with the mighty blows of two titans, changing the dynamics of a fight with a set of lackies. Their powers surge just from being near a font of unfathomable quantum energies, making it difficult to control the force field they're using to protect civilians. The bright lights of their conflict act as a local strobe attack, imparing a player's ability to spot an assassin before it's too late. The Non-Player Characters are only important in that they affect what the Player Characters are doing.
Since you can't focus extensively on NPCs, you have little opportunity to characterize them. Even if you put them in a role where interacting with them is natural and important, like when they're used as a gatekeeper or a quest source, they tend to be seen in that light alone. Having fewer NPCs means that you can spend more time to develop each one and make them into memorable, well-regarded characters. Then, the treachery comes.
Implicit in this is team unity. No one likes the artificial feeling that your characters are just working together because it's easier to run the game, but there it is. Shit happens. A good storyteller can dress it up a bit, but that's exactly what you're looking at. Spreading out your team increases all of their social contacts, their settings, etc., etc.. When they're together, they can share a series of acquaintances and villains, while they can still have an NPC or two on the side to help flesh them out.
In both tone and frequency of play, if you just play, rough spots will take care of themselves. That's partially what the humor is for, really. Three sessions with a 'meh,' story, equitable storytelling, a few familiar characters, and clear action will be better than one good story with all of those things. Most people just want to play. If nothing else, there's little better in terms of learning the rules than actually making players search for them in a futile attempt for their characters to survive.
If you do have an epic, amazing, fantastic story to tell, one which pierces to your very core as you feel its roots penetrating your heart and see its delicate branches caressing your core book, you should probably make that story a novel and keep your players away from it forever (I've heard that Stephen King still hasn't told his players about The Stand). In all liklihood, my next Novel Writing Month exercise will, in fact, be the beginning of a series of New Port City stories. Roleplaying stories are short and give characters the chance to add a completely random element to the mix. They are about the characters, and characters are to delicately woven stories what hormonal armored bulls are to china shops; immune to all forms of insurance.
Parts One and Two.