Well, the most important NPC of the plot is the antagonist, in my mind, so I always go out of my way to have one or several developed with the appropriate motivations as my means of laying the groundwork of a plot. "Why?" is often used to flesh out the who of that particular NPC. I'm not sure I view them as NPC's so much as secondary characters in a sense.

Speaking of NPC's, I do have an RP setting that I do an RP for, from time to time, where magic-users (it's modern) call their mundane, non-magic using detractors "NPC's." It's a bit of an insertion of nerd humor in there.