I can't imagine what I have is horribly original but humans are the "newcomers" in my current homebrew. Just a head's up, I do utilize a number of the elements from 4e's default setting.
The first humans arrived in a crashed spacecraft about 2,000 years before the common date. For those who play WoW, the spacecraft was a great deal like the Exodar of the Draenei. Magical more than techonological.

As refugees from a tyrannical society, they came to the conclusion they had no desire to leave the world so they made efforts to remain. The race settled near the crash site, on the island of Nerath, which had been unclaimed for various reasons. After about 300 years of meeting new races, breeding with them (humans can interbreed with any race, the inverse is not true), and setting up strong ties their king decided to take a more direct role in the world stage.
Humans were the impetus for the development of the Imperial Republic of Nerath, which at first blush seems like a contradiction, I know. It was an alliance (partially inspired by Republic Era Star Wars and partially by the Roman Republic) designed to unify nations and promote growth and prosperity. Members agreed to give up some of their governmental control (mostly in the area of public works), to recognize the Nerathian king as a first among equals, and to adhere to a certain law code in exchange for representation in a vast senate. This senate would regulate trade, open trade networks on this world and others, broker deals, establish extraplanar colonies, etc. on the behalf of member nations. All allies would reap the rewards of this ever expanding alliance.
In time, the Imperial Republic would extend over most of the continent and nearly every nation had representatives in the senate. Despite all this, humanity never constituted more than 15% of the total population of the alliance. And after its fall, that total dropped significantly. The Imperial Republic of Nerath fell apart at its height through circumstances they could not control. So many nations depended on the alliance to maintain their roads, trade relations, and other luxuries they couldn't cope. As the Imperial Republic faded to dust, so did a number of nations that had stood for centuries. In some places, the current state of affairs is directly blamed on humanity, which is actually rather justified.
In the modern era, humanity really only exists in large numbers in two locations. First, in the island chains located around the now sunken island of Nerath. Second, in the Valelands, an area colonized by humans during the Imperial Republic (Nentir Vale sits in the Valelands, by the way). If some people had their way, humans would be wiped out entirely.
Some of this is a total clone of things that have come before. But then, I have always been a fan of "creative borrowing" when I feel it would work for my game.
