The relative contribution and source of the fuels used during endurance exercise is dependent on the intensity and the duration of the exercise. Much work has been done to investigate the potential performance-enhancing effect of manipulating training and dietary interventions in athletes, as well as the influence of gender. Studies show that even patients with metabolic myopathies may derive benefits that counter the age-associated loss of muscle mass and strength. This article gives an overview of these different impacts on endurance exercise, concluding with an examination of the metabolic myopathies that impair substrate metabolism in skeletal muscle and result in exercise intolerance.