The 07+ engines will get better fuel economy (but you'll have to deal with a 10K dollar muffler). The 04-06 engines were overfueled to bring combustion temps down and reduce NOx. The 05-06 CAT engines (specifically C15's) had way retarded timing so they were doggy off the line and also got poor fuel economy. The C15 bridge engines (5 and 6NX engines IIRC) are the ones too look for. Either that or go a bit older and get an electronic 3406 (just b4 the name chagne to C15) factory rated at 600HP, then have it turned up. If you want MPG don't buy a CAT. If you want to pull hard you'll have to buy the fuel and get yellow iron.
We don't have a ISX in the fleet that will keep up with our C15's regardless of the version of the ISX. Not saying it's a bad engine (although they did have some major issues with them. There are updated parts to fix it all though $$$$).
ISX is probably ok in a OTR truck, but we abuse them a bit more than that. The ISX's won't keep up at 50-80K pounds, and when you get out around 100/150/200,000 pounds the ISX just plain falls on it's face. The C15's don't mind. If you want MPG get a Series 60, good engine, great MPG. They aren't power houses though. The 14L S60 at 550HP still only makes around 1500 ft/lbs, but it'll get 5-9mpg depending on the driver and load. I've seen Series 60's with over a million miles without ever having to touch the long block.