Increased non-oxidative and oxidative ATP production via metabolic pathways in skeletal muscle is essential for the maintenance of force and power production during exercise. However, substrate depletion and accumulation of metabolic byproducts are potential causes of fatigue. Reduced PCr availability can limit power production during sprint exercise, whereas carbohydrate depletion is a major limitation to endurance performance. During sprint exercise increased Pi and H+ may contribute to fatigue, and during prolonged strenuous exercise, the accumulation of NH3, reactive oxygen species, and heat can limit performance. Appropriate training programs and nutritional interventions are potential strategies to enhance fatigue resistance and exercise performance.