Motivating the characters to oppose the villain.
The last successful campaign I ran started with the PCs on the run from the evil empire because they were spellcasters, and the evil empire wanted to kill all spellcasters who didn't belong to a particular imperial organization. Forced together, the party was motivated even if they didn't get along. That campaign was great, as eventually the PCs grew to like each other.
The next campaign I started had a similar 'on the run' beginning, this time when a military quartermaster framed the party for stealing magical loot, and had them run out of the military, with bounty hunters on their tail. However, I made the mistake of having the villains not be at all associated with the military. I figured I'd have them be on the run, and then they'd stumble across a secretive plot, so they'd have to rely on themselves to stop it, since they couldn't go to the authorities. Well, instead the party ignored all hints at the plot, or when they did follow the hooks, they were just doing it because they were frustrated, not proactive.
That game collapsed, since the party eventually decided to become murdering pirates instead of follow the plot hooks the entire campaign setting was based on. I suppose I could've just jumped forward in time a few months to when the villains succeeded with their nefarious plot, but I didn't like the characters.
My new game, the party seems to like short adventures, not villainous plots. So I'll just think of several possible villainous plots, and run the characters through various adventures tangentally related, until they seem to get interested. The group apparently wants to join a rebellion of some sort, so I need to come up with a revolution.
One of the persistent problems I have is that the players just aren't curious. They see someone or something, and if they think it's a bad guy, they attack it. Even if it's not a bad guy, and the person asks them to stop attacking, they keep attacking. If it is a bad guy, so far even a CR 14 demon hasn't been enough to do more than tickle the 10th level party, since he spent the entire encounter on the ground thanks to Mr. Spiked Chain.
Sorry, ranting.
Anyway, the party doesn't seem to care why villains do what they do, or who they're working for, which makes it very hard to have any sort of involvement by the villain, barring the villain just walking up, slapping the PCs, and saying, "You idiotic fools! I. AM. THE. VILLAIN."
And if he did, they'd just trip him, take 18 attacks of opportunity on him when he tries to do anything, and then beat him to a pulp.
The players just want a video game. It seems like a waste.