Now, the biggest change is not in game mechanics, it's in cosmology. They reworked things to make D&D more accessible. Greyhawk is no longer thesetting used for flavor text in the book, they instead went generic. So, the cosmology and such presented in the book is what is in any and all worlds that are part of the D&D universe. Anything additional is just that, additional. Makes things easier on world builders like myself. This has sparked me to consider a few things about the cosmology of the world of my fiction.
Na'Shenassi has always been based in a D&D universe, and as such, I feel compelled to examine the new aspects of that universe and meld those things that I think are worthy, and that's a good 90 to 95% of the new content. So, I've found that I can make some really amazing changes to Na'Shenassi that add much more flavor. Most notably is the inclusion of the Shadowfell, the plane of shadow revamped and the place where all dead souls travel before moving on to their individual afterlives. The Raven Queen actually fits into a slot that was previously kind of flimsy and didn't really have anything fleshed out around it. As a result of this, I have to create a new race, but this seems surprisingly easy.
My recommendations are this: If you play PnP fantasy RPGs, then D&D 4th edition is a must buy.