I've been avoiding this thread because the premise is too depressing.

To think what might have been...
To me, the main story arcs would be built around Mal on the one hand and Simon on the other. Those were the two characters who had the most character growth in front of them, and that growth should be the major driver of the plotline.
Mal needed to get over his bitterness and go back to the idealist that he was in the war. Simon needed to shuck the last vestiges of his privileged place in society, continue the process that started when he rebelled to save River, and in essence become a Browncoat.
The other characters would have roles in the story based on their relationships to Mal (Zoe, Inara) or Simon (Kaylee, River). And of course Jayne is just Jayne and is in it for the mayhem, tho I would love to see his relationship to both Mal and Simon developed as those characters change. Jayne trying to deal with the notion of Simon being more of a badass (more of a badass than Jayne, really - I think the guy had it in him) would have been golden.
It would have sucked to continue to story without Book or Wash, but I guess I can live with that. Makes it a pretty female-dominated cast, and that's interesting for a change.
Basically, this is the stuff they should have done:
SEASON THREE:
The consequences of the Miranda broadcast unfold. Though the Alliance has been able to fool most of the worlds under their control that the Miranda broadcast was a fake, it has hit a patch of difficulty trying to convince the rim worlds of the same thing. A rebel movement, made up of former Browncoats who refuse to give up the fight aganist the Alliance, use this as an opportunity to start a second War of Independence. This is the same movement that helped Simon rescue River but for the reason of using her as a weapon aganist the Alliance, which Simon was opposed to and took her from their clutches before they had a chance to try.
...
In the seventh episode, Simon feels the time has come for them to involve themselves in what's going off-world while Mal feels they have done enough with the Miranda broadcast. This splits the Serenity crew into two. Jayne, River, and Inara on Mal's side, and Zoe and Kaylee on Simon's side. By the end of the episode, Simon takes one half of the crew with him off-world while Mal and the other half stays on the planet.
If the show had run for 5 years we wouldn't have got Serenity, so I'd discount those events.
Yeah, we really need both Wash - the "common man" - and Book - "the mystery man" - on the series. Those are both great types to have in the mix.