Another point to possibly consider is support services - generally, gas, food, medical care, repairs, etc etc will be more concentrated along interstates, especially in the wide open spaces out west (notwithstanding that stretch of I-70 where you go 105 miles between exits...) Out on the blue highways (or Blue Star highways, which not all blue highways are...) if you break down, it may be a longer wait for service.
There are benefits to using either - Interstates for speed and convenience getting from point to point, less formal highways and byways for scenery, local flavor, and (in most cases...) lower blood pressure.
