During submaximal endurance exercise, women oxidize more lipid and less carbohydrate as metabolic substrates than men. This is reflected in a lower glycogen utilization in skeletal muscle and lower hepatic glucose production for women compared with men. These latter observations may explain the lower leucine oxidation observed during endurance exercise in women. Animal and preliminary human study evidence suggests that 17-β-estradiol may be a major determinant of the sex dimorphic response in carbohydrate metabolism during exercise. From a practical standpoint, it appears necessary for women to increase their dietary energy intake (and percentage derived from carbohydrates) for four days before a sporting event in order to supercompensate muscle glycogen concentrations. Sex differences in carbohydrate metabolism may have future implications for the care of patients with diabetes and inborn errors of lipid metabolism.