As much as people like to play the asshole card in stuff like Fallout (my friends have often shown nothing but contempt when I buy things from stores rather than stab everyone, stack the bodies into a human pyramid, steal everything, then decide I don't want any of it anyway), it's harder to relate to a story when you're the antagonist. If you want to make a meaningful story, then you're probably going to need better motivations for your villainy than moustache-twirling, tie the damsel to the train tracks, meaningless malevolence. However, that sort of approach doesn't seem right either, I mean, people have probably bought this game just to be an evil ass and wreck stuff like the Hulk on cocaine. So then maybe you DO want pure, unadulterated chaos to be your villain's motive, or something like the old 'world-domination' chestnut. It's a difficult project to approach, and it's easy to have so much evil at your disposal that it just loses all weight. Some games are able to pull it off every now and then, but if it was that easy then more people would have created them.
Personally, I enjoyed Dragon Age: Origin's approach, which was to give you multiple options to choose from, but not just label them things like 'good' and 'bad,' which gives you the opportunity to set up moral dilemmas, where there is no 'right' answer. Do you kill a young, possessed boy, or sacrifice his mother so you can confront the demon possessing him and spare the boy's life, or do you travel for help, but risk the possibility of the boy killing more people in your absence? I realize that was something of a digression, but I doubt many villains simply label themselves as 'evil,' and generally have their own justifications for their actions, so making a player go through the same process, committing heinous or forbidden acts for a cause they believe in (or just giving them the option to be 'Captain Asshole'), is perhaps a good compromise to the dilemma I suggested.
And no, I'm no expert, so by all means, point out all the holes in the logic I just set forward. There's probably some gaping ones.