"Prophecy Rule. Any ancient prophecies are always correct. Also, if they mention Chosen Ones who will save the world, the players will be it." taken from here.
Ok, so it would entertaining to run a game in which the players are witness to a prophesy, and either misunderstand it, or the prophet is just dead wrong. The players of course need to be in on the joke, otherwise its just the DM being clever and the players being angry, but the game consists of their (mis)adventures, trying to complete this misunderstood quest, or perhaps even trying to race the real Chosen Ones to the Amulet of Doom or whatever.
Imagine if you will a group of dwarves thrown into the Lord of the Rings saga who believe that it is their destiny to deliver the ring that Grandma Stone-beard gave them into Mount Doom.
(tone: dark comedy)