Muscle glycogen and blood glucose are important substrates for contracting skeletal muscle during exercise. The possibility exists for considerable interaction between muscle glycogen and blood glucose and their effects on muscle glucose uptake and glycogenolysis, respectively. Increases in blood glucose availability have little effect on net muscle glycogen utilization during prolonged, strenuous cycling exercise, but this may be dependent upon the mode and intensity of exercise. No data exist on the direct effect of reduced blood glucose levels on muscle glycogen metabolism. In rats, studies using the perfused hindlimb suggest an inverse relationship between muscle glycogen levels and glucose uptake. A similar conclusion can be drawn from a number of human studies albeit, on occasion, from indirect evidence. The influence of muscle glycogen on glucose uptake involves effects on both membrane glucose transport and intracellular glucose metabolism. Such a relationship would, under conditions of adequate muscle glycogen availability, limit muscle glucose uptake, thereby preserving the relatively small blood glucose supply for the brain, nerves, and blood cells, which are dependent on it for their energy metabolism.