Al Scott Lecture. The ability of the circulatory system to adequately match blood supply to tissue demand implies the existence of regulatory mechanisms that communicate tissue status to blood vessels. For example, red blood cells have been shown to respond to low tissue oxygen levels by releasing ATP. The ATP triggers a conducted response signal to travel upstream and cause arterioles to dilate so that more blood is delivered to the region of demand. A theoretical model focusing on the role of this mechanism in blood flow regulation is presented here. In the model, arterioles control blood flow by dilating or constricting in response to changes in metabolism as well as to changes in pressure and wall shear stress. The model predicts that responses to these three stimuli can account for the increase in blood flow that occurs with increased oxygen demand.