Adaptation of blood flow during the rest to work transition in humans. Med. Sci. Sports Exerc., Vol. 31, No. 7, pp. 1019-1026, 1999. Beat-by-beat measurements show that limb blood flow rises rapidly and in a biphasic manner at the onset of rhythmic exercise in humans. In this review the time course of change in limb flow with the onset of exercise is described and the mechanisms that may or may not contribute to its regulation are discussed. The pumping action of contracting skeletal muscle appears to form an important regulator of increasing flow with the first contraction. However, evidence from human studies suggests that vasodilation begins with the first contraction. Whether this early dilation is regulated by neural recruitment of motor fibers and/or muscle contraction per se is discussed, but the mechanism(s) remains unclear. Finally, the contribution of endothelial-derived relaxation factors to the exponential increase in flow at the exercise onset is examined. Based on studies in humans with intra-arterial infusion of blocking drugs, neither acetylcholine, nitric oxide, nor prostaglandins appear to be essential for a normal dynamic flow response on going from rest to exercise. Overall, evidence from human studies supports the hypothesis that the rate of increase in blood flow during rhythmic voluntary exercise is closely coupled to motor unit recruitment with dilation beginning at the first contraction.