Diabetes constitutes a global emergency with case numbers increasing exponentially every year. Diabetic foot ulcers are the leading cause of nontraumatic lower limb amputations. A complex background of pathophysiologic events has been identified with advances in molecular biology such that newer interventions are possible. Bioengineered skin substitutes currently play an important role in the diabetic foot ulcer, particularly in the "stalled" wounds that fail to show progress in their healing trajectory. However, newer designs and scaffold incorporation may herald a new generation of products with more focused targeting of these pathophysiologic events. The major background impairment is that of vasculogenesis brought about as a direct result of hyperglycemia, advanced glycation end product/methylglyoxal generation, and its direct effect on endothelial progenitor cell production and attraction to the wound site. At the same time, glycation end products affect immunity and inflammation, increasing the susceptibility to infection. Thus, reactive oxygen species scavengers, methylglyoxal scavengers, vascular endothelial growth factor stimulators as well as various lipids and neuropeptides are all potential agents that could be incorporated into such templates. The logical sequence of events and possible interventions is detailed. In this manner, intrinsic healing is encouraged in preference to our current attempts at adding unknown quantities of specialized cellular and growth factor components which seem to provide very temporary advantages.