The number one thing is making as much power at a given cruise condition, at stoichiometric, as possible. Rich is not burning all the fuel. Although slightly lean can get better fuel mileage, it causes more emissions, and if we are talking a 427 FE the combustion chamber design will not tolerate lean burn without pinging. So what does that leave us with? Getting the timing right! The number one MPG killing thing I hear people do, is they don't use vacuum advance. That's fine for all out racing, but no good for MPG.
Nothing will allow you to dial in the best timing at a given condition like EFI. It also allows you to dial in the fuel. You should try to target a slightly lean condition at cruise conditions and then find what timing gets you maximum break torque (MBT). If it pings, you have to go richer towards stoichiometric. If it doesn't ping you can try going leaner. Note that as you go leaner you will need more advance, so you have to find MBT again at each fuel ratio change.
Tune and valve timing is your biggest opportunity.
Other things:
1) thinner
synthetic oil. Engine, Trans, & Differential.
2) lower volume
oil pump. Wastes less energy, too little and by by engine.
3) pump less coolant by slowing water pump, if you can. Watch temps.
4) parasitic loss from belts. Many designs out there. Do your research.
5) Tires. Bending rubber wastes energy. Narrow low profile tires wast less energy.
6) Gearing. Cruise rpm should be lowest RPM engine can tolerate.
7) low friction rings.
8) Cam that allows engine to tolerate lower cruise rpm.
9) Reduce rotating mass where possible.
All these thing have trade offs. Narrow tires, not good for traction. Low profile make a harsher ride (feel driving over a grass hopper). Looks may not be as pleasing. The cam for best MPG is not going to make as much power, nor will it have the rumpity rump idle that we love.
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