Okay, I've had some experience with players taking a game in completely new directions. Usually as one of those players...anyways. I've heard the author of a Live Action game, who was finally able to play in his creation, wailing 'I wrote the thing, and I don't know what's going on!'
Plan on having key events that will happen, regardless of what the players do. Volcanoes erupting, warships showing up, what-have-you. Plan on the fact that the players will surprise you, to the point of systematically dissecting a problem (or bad guy!) to try to find the right way around it (or the ring of regeneration he's swallowed).
If the players head off in the absolute opposite direction from where you want them to go, send in a friendly reminder (like an NPC, or convenient landslide) that Something ImportantTM is going to happen 'back that way'. Oh, and on the topic of NPCs, it's important not to make them the 'go-to-guys' for all the players problems. Players have to feel needed, or else why not let the NPCs take care of whatever big event is going on?