I've been considering building a super-high-mileage machine quite a bit for the past five or six years. Now, with gas prices going up... I've been thinking about it more and more.
The basic concept is to take the lightest possible platform and put in an already efficient engine.
So, my thought process has taken me to something like a Mini or Audi 500 or 600 (all of which weigh around 1400 pounds or less). The nice thing about these is also that they are old enough (1960s) to be easily modified without running into problems with emissions laws (at least here in VA). They aren't the most aerodynamic possibilities, so I am open to other recommendations for possibilities. In stock form, these will put down 40-50mpg.
Then, I would plug in either an efficient motorcycle engine and gearbox or possibly the D15Z1 engine from a mid-90s Civic VX. The motorcycle engine combo would probably shed some weight (a nice plus), but these engines weren't really made to pull 1400 pounds and therefore might be overburdened. The VX engine is a nice possibility because it already gets 50mpg highway while pulling a 2300 pound Honda. It is certainly up to the task and would probably see a bit of a mileage improvement with close to a thousand fewer pounds to pull.