It looks to me like wind is not simulated in the EPA tests; dunno how big a factor that is but I know that the formula for wind resistance goes up by the *cube* of the speed.
I think that they might calculate it in somehow. My 4WD Explorer was rated at 16 city and 19 highway (full-time FWD, no way to disengage the front hubs) and that's what I got. Likewise, my Escape gets within 1 mpg of the ratings for each type of driving. I keep records of my mileage as its a good indicator when something is going awry.