A variation of Ockham's Razor should be applied to all fantasy football decisions: the simplest, easiest choice is also the best. Don't out-think yourself; do what is logical and obvious rather than trying to be clever or smart.
I could have drafted Ladanian Tomlinson with the #2 pick before this season. That was a smart, safe pick. But I was all hyped up on Clinton Portis: he's consistently good, he'd have Al Saunders' system, and I wanted to be the one smart enough to get him. So I traded down to gain an earlier 3rd round pick and took Clinton Portis at #4. This trade helped my brother to what looks like an easy championship, and it clearly cost me.
Don't try to be clever at draft time. If you have to make the obvious choice, just do it. You'll look smarter when you actually win.
The same rule applies to starting lineups. Don't overthink matchups. This week, I thought Shaun Alexander, who had been struggling, would lay a total dud against the good Charger defense. Meanwhile, Travis Henry was going against Buffalo, a team that had some weaknesses against the run. Well, Henry did have 135 yards. But Alexander had 140 yards and 2 TDs. Don't ever talk yourself out of an obvious stud.
This is the #1 rule of Fantasy Football. Other rules will follow.