Insulin vasodilates skeletal muscle vasculature via an endothelium-derived nitric oxide-dependent mechanism. Data suggests that insulin interacts directly with the endothelium to cause nitric oxide release. This insulin-mediated increase in muscle perfusion accounts for approximately 30% of insulin's overall action to stimulate muscle glucose uptake, suggesting a role for insulin and glucose delivery as a determinant of insulin action. Hindlimb perfusion experiments, where perfusion rate is fixed, suggest that changes in distribution of microcirculatory perfusion can modulate substrate uptake. The potential role of insulin to enhance flow through capillary networks that are efficient at nutrient transfer to tissue (nutritive flow) relative to non-nutritive flow is discussed.