The primary function of the cardiovascular system is to supply oxygen to tissues and organs in the body. When muscles contract the aerobic demands are met by an increase in oxygen delivery both at the systemic and the regional levels; a match that is very close and holds at submaximal exercise and when small muscle group contract also at vigorous intensities. The level of muscle perfusion reached is 250 ml min-1 100 g-1 in muscle of sedentary subjects and in endurance trained athletes 400 ml min-1 100 g-1 has been reported. These levels of exercise hyperemia equal what has been observed in other species. One consequence of these high muscle blood flows is that the human heart cannot support an optimal blood flow in whole body exercise (arms and legs combined) and sympathetically mediated vasoconstriction, also in arterioles feeding active limb muscles, contributes to match peripheral resistance in order to maintain blood pressure. Respiratory muscles appear to have a higher priority for a blood flow than limb and torso muscles. There is no consensus in regard to which locally produced substances that elicit the vasodilation when muscle contracts. In addition to NO, data are presented for various metabolites of arachidonic acid and on ATP, possibly released from the red cells. Using blockers of NOS (L-NMMA or L-NAME) and the enzymes producing EETs (Sulpaphenozole or tetraetylammonium chloride) or prostaglandins (indomethacin), muscle blood flow may be reduced with up to 25-40%. Evaluating the exact role of ATP has to await further studies in humans and especially the use of specific ATP receptor blockers.