building a long distance touring car

adding this or changing that,run this gear and the small engine is better are just generalizations and can work but i know guys who have added over drive transmissions and got worse mileage.
and i know 2 bbl 318's that got poor mileage and stock tired 340's with 3.23 gears that got lo 20's
Rumble is correct about the cam, and hi lift short duration can work for power and efficiency.Cam is very important.
The engine must be super efficient, especially at cruz rpm.So head design and flow, valve size,intake manifold and carb flow,compression,exhaust,gears, tire ratio, converter are different for each engine size,and on and on.
...this requires a lot of thought
there is an old blog floating around the inter web somewhere called hot rod Daves super duper mileage
miser or some thing similar.A year long experiment with a tremendous amount of tests, parts and results!
Let us know how you make out!