The magnitude of the blood flow to the skeletal muscle and thus, the oxygen delivery is closely regulated. Indeed, over a broad range of oxygen demands, from rest to intense muscle contractions with small muscle groups, the "coupling" is very high (r-r² close to 1.0). The regulatory issues related to the matching of systemic and regional blood flows are in parts understood (1). What is not known, however, is what causes exercise-mediated hyperaemia. Indeed, listing mechanisms or substances that have been proposed and studied over more than a century could fill this abstract. It is true that NO is the major player in overall vasodilatation in various tissues, including resting skeletal muscle. During muscular contraction NO still plays a role, but it is in combination with other and possibly more active vasodilators. Prostaglandins and nucleotides, as well as adenosine, appear to be most critical (2); the latter primarily enhancing the effect of NO and prostaglandins (3). ATP may play a double role, both as a vasodilator acting via its binding to endothelial purinergic receptors and also by impairing or inhibiting the sympathetically induced vasoconstriction (4). The source of the ATP is unsolved, but with the challenging possibility that the ATP is released from the red cells as a function of a lowered number of O₂ Hb binding sited being occupied, i.e. the red cell acts as an O₂ sensor in the microcirculation (5). So what is new? The endothelial purinergic receptors and their activators! ATP has been identified, which with other nucleotides, nucleosides, and prostanoides may well be shown to explain a dominant fraction of the hyperaemia. Moreover, this metabolically mediated vasodilatation is active already after 2-3 contractions. References 1. Saltin B. J Physiol 2007, 583: 819-23 2. Mortensen SP et al.. Am J Physiol 2009, 296; R1140-8 3. Mortensen SP et al. Hypertension 2009, 53: 993-9 4. Rosenmeier JB et al. J Physiol 2008, 586; 4993-5002 5. González-Alonso J et al. Circ Res 2002, 91; 1046-55