Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation.