Well, here's what I've come up with as a solution. I'm going to vent everything from the ceiling. I've done my calculations for CFM and think I can make this work out very well. I have easy access to run two vertical stacks from the main plenum. One will route up to the attic to dispense to the 3 upstairs rooms (planning on 2-3 ceiling vents/room). One will route up to the first floor ceiling next to the upstairs ducting. This gives me access to about half of the first floor ceiling spaces, but I might have to be creative in concealing the ducts. The other half of the first floor will be run through a third set of ducts that I "should" (am I the only one that absolutely hates that word?) be able to conceal that riser into the attic (behind upstairs knee walls) to run ducting to that half the first floor. As it is, the house only has about 1200 sq. ft. of floor space to condition.
I decided to go with the ceiling venting because I'm in a climate that can get below zero, but doesn't do so that often, and I tend to be warm to begin with. At this time, I don't have central air, but that will be a later add-on. With ceiling venting being better for central air, I'll be better served, as keeping my cool is much harder for me to do.
My plan for runs is to use insulated piping and then to go the additional step of "boxing them in" with rigid foam insulation, especially the verticals and attic areas. I am still tinkering with the idea of routing all my return air into the crawl space (after installing heavy vapor barrier and insulating it. I'm also toying with the idea of running a perforated pipe drain system around the exterior of the crawlspace under the vapor barrier. I can do so and have it come through the wall directly into my sump, in case water comes up through the ground. The constant in/out air flow (in at the far corner and out at the near wall, as far apart as physically possible) should keep the area moderately conditioned and dry. As this is the area directly underneath my bathroom, that should help keep the floor from being ridiculously cold in the winter (going with ceramic tile, but not sub-floor warming).