The 'crossover' and 'lactate shuttle' concepts of substrate utilization in humans during exercise are extended to describe metabolic responses on other mammalian species. The 'crossover concept' is that lipid plays a predominant role in sustaining efforts requiring half or less aerobic capacity (VO2max); however, greater relative efforts depend increasingly on blood glucose and muscle glycogen as substrates. Thus, as exercise intensity increases from mild to moderate and hard, fuel selection switches (crosses over) from lipid to carbohydrate dependence. Glycogen and glucose catabolic rates are best described as exponential functions of exercise intensity, but with a greater gain in slope of the glycogen than glucose response. In contrast, plasma free fatty acid flux is described as an inverted hyperbola with vertex at approximately 50% VO2max. Both endocrine and intra-cellular factors play critical roles in determining substrate balance during sustained exercise. Moreover, genotypic adaptation for aerobic capacity as well as phenotypic adaptations to short- and long-term chronic activity affect the balance of substrate utilization during exercise. The concept of a 'lactate shuttle' is that during hard exercise, as well as other conditions of accelerated glycolysis, glycolytic flux in muscle involves lactate formation regardless of the state of oxygenation. Further, according to the lactate shuttle concept, lactate represents a major means of distributing carbohydrate potential energy for oxidation and gluconeogenesis. In humans and other mammals, the formation, distribution and disposal of lactate (not pyruvate) represent key steps in the regulation of intermediary metabolism during sustained exercise.