My new setting is built around exploration of unknown lands. There is one "known" continent, which is divided by a vast mountain chain into two distinct parts. One is a human dominated civilization, consisting of 13 city-states which are all ruled by a central theocratic government. The other division is a vast and largely uncharted wilderness dominated by non-human races, many of which have great resentment for the citizens of the human civilization that drove them across the mountains hundreds of years ago.
The rest of the world is more or less unknown. The planet is large, and crossing the oceans is difficult. As such, one is far more likely to discover distant lands in myth and legend than on a map. However, that's not to say that those lands aren't there.
My first campaign will start within the human civilization, and will probably spend the better part of heroic tier within that region. When the PCs are ready, they'll move on to explore the wilderness across the mountains, where danger is much more constant and more deadly (Points of Light are very few in this place). When they've had their fill of that, they'll be able to sail to new lands, which will have new civilizations and strange things to discover.
I'm hoping that this emphasis on discovering the unknown will allow me to take advantage of 4e's superior "on the fly" capabilities, as well as giving the players an experience that they really can't get when playing in a setting that's already detailed by a large book. I think exploration can be far more meaningful when you have absolutely no idea what you might find.
Also, it gives me the opportunity to have many very different areas in the world. There might be continents with civilizations that are far more advanced than the known human nation. There might be lands where orcs are peaceful and elves are war-like. Isolation of world areas makes for a much larger possible variety of experiences. Much like earth was before western culture started to overrun everything.