Lots of comments here echo things I've discovered driving my 2007 1/2 ton...for the past 15 years. Glad I'm not the only one who knows them.
Tires. I think I lost a bit of mpg (maybe 1) going from Firestone Destination LE2s to Cooper Evolutions, but I don't mind 'cuz the Coopers are H rated, which I wanted. And the Coopers are made in USA.
. It's hard to say on the mpg, 'cuz I also went from 275/60s to 275/55s.
Someone mentioned they have 17s. That's the lightest wheel setup, and what Dodge/RAM put on the HFE (high fuel efficiency) edition. The best are these part numbers: OZR75TRMAA; 0ZR76PAKAA. Factory forged 17".
Transmissions. The "new" six speed (65RFE) is the same old 545RFE. (But programmed to use 2P as third.) Save for some HD trucks that got the 66RFE... Slightly better ratios there, but not like the 8-sp. Both an 8-sp auto and a 6-sp manual are worth 2mpg from the research I've done, but you wouldn't expect either swap to pay you back quickly. Why? I figure on AT LEAST $3 grand (w/used tranny) to get either swap done; probably more. So, $3,000 / $5 a gallon = 600 gallons. That's how much you'd have to save to get the payback. 2mpg increase is going to square out to...probably something crazy like 120,000 miles of driving. Could be a while.
Oil. I've always run synthetic since the 1500 mile mark on the odometer. Rolled over 160,000 this month. Generally Mobil 1, in the 5w-30 flavor. I know the manuals call for 5w-20 (even for my 2007), but that's because they are using a slightly thinner oil to squeeze out a little less parasitic pumping loss to improve mpg a teensy bit more. I also run my oil to 7,000 changes. Yes, I did an oil analysis years back, and the oil in my pickup was fine at that point. I still run a FilterMag on the oil filter also.
Radiator fan. Electric will save you some parasitic hp, which means you burn a little less gas. No, I don't have an exact figure.
Underdrive pulley. According to ATI, theirs is worth 8-10hp at the crank. 5-8hp if you do not have a clutch fan.
Thermostat. You have to be mindful of the PCM programming here. Too cold, and it'll always think it's the in warm up cycle...and enrich the mixture.
The opposite is also an issue. The engine gets warm enough, and the PCM starts pulling timing. I think I'm encountering that now, as my radiator won't hold much pressure. I see temps 203-210 regularly right now. Got a 100% aluminum radiator with welded tanks on order... I also ordered a FlowKooler water pump, but didn't install it once I saw the radiator was leaking.
Aerodynamics. First off, the frontal area of our pickups, at least my 07, is 34 sq ft. A full sheet of plywood is 32 sq ft (4ft x 8 ft). So, that's like pushing the proverbial barn door down the road. And, with a 3rd gen, the aerodynamics suck even more, save for the SRT models. Look up drag coefficients...
Someone mentioned a tonneau cover; yes, that does help. I think it's worth 1mpg on the highway. A bed topper does the same, but since they weigh more, you use more fuel when climbing hills. I've tried it both ways in drives up and down I-44 through Missouri.
Wheel covers. Remember the old moon eyes wheel covers? Those do help. I have some (homemade ones) on my pickup. Another 1mpg on the highway. In fact, per the NACA article mentioned earlier...they probably take effect at or near 48mph, if I had to guess.
I also have most of the belly covered from the front bumper to the rear muffler. It's not a monster gain, but probably another 1mpg highway.
Fuel. Can you get 100% gas? E-10 drops about 10% on fuel mileage. In my highway testing, with a tune adjustment, I saw another 1.5mpg with a 91 tune over an 87 tune. 91 and 87 octane fuels used respectively. E-85? Ouch, count on a 30% drop. And...your fuel system needs to be designed for it, or it will eat up the seals.
Cruise control. Do not use it on hills. Talk about chug-a-lug fuel. (How do I know? I have a fuel flow meter.) Hit the cancel button with your foot positioned so you can maintain the speed you are at...and as you climb the hill try to only let the pickup lose about 5mph or so while climbing. Some hills in MO, CO, and UT you really can't do that, but most you can. You can pick the speed back up on the other side.
Injectors. Depends on what you have to start with. My 07 had 4-hole injectors; I upgraded to Bosch 12-holes, but think radiator/heat issues are preventing me from seeing any gain. They must atomize fuel better, because I get a CEL regularly that complains about being too rich.
Driving habits. Most certainly! As they say one the Ecomodder forum "Adjust the nut behind the wheel." Don't launch hard at every stoplight. Don't panic brake. Some say to drive like there's an egg under the throttle. Coast! I sometimes can coast 1/4 to 1/2 mile before I have to hit the brakes for a full stop. True, the engine is running, but it's only burning about 1/3 to 1/4 of what it does when you've got your foot on the gas. Another phase is "Driving without brakes." You do have brakes, but act like you do not, or don't want to use them. **I do NOT advocate shutting the engine off and coasting. ** Too much can go wrong with that.
Yes, these apply to any vehicle. Yes, your mileage WILL vary. With my cooling system running right, I've seen 21mpg highway at 70mph. On a 600mile trip. If I could get it to 25mpg, I could go without a refuel!