First, welcome to the forum JayD. That S10 chassis swap seems to be popular in your area - I saw at least two different trucks using that chassis in the Ponca City area some time back.
I have Edelbrock's ProFlo XT system and once dialed in I like the ability to tweak tuning or parameters like the cold start curve via a laptop. To get it dialed in I consider it mandatory to use the laptop programing interface, and an experienced tuner who understands all of the variables. Trying to tune across the load range using the procedure they give for the hand held programmer would be very, very difficult and time consuming, requiring a driver and a second person to watch the unit and take lots of notes. If you don't have access to a dyno and a good tuner I would look to one of the self learning units like the ones from FAST or Holley if you're going aftermarket, and you're still going to spend several thousand dollars to get it done right. Like 1gary says, I would avoid the used aftermarket units like the plague - nothing but headaches if you don't have factory support, even if you're just looking for good economy vs top performance.

Good mileage is driven by your tire size, rear gears, good OD ratio coordinated with your cam and power curve; and then keeping your foot out of it If your engine is stock, I would think that shooting for a nominal 1750 to 1800rpm at your highway cruising speed would be about right, especially considering the Oklahoma rolling plains terrain. Based on what you've said about economy being king the stock TBI EFI would work fine, coupled with the right gears and OD tranny. You could even keep the OBDII diagnostics port with the right harness & stock PCM. If you're more of a carb guy then I think you can still get the mileage you're after with the right driveline combo and an egg under the throttle pedal. Just my $0.02, and more pictures would be great, too!