This review considers four experimental models for studying the dynamics of ammonia and amino acid metabolism in skeletal muscle: the rat hindlimb, the isolated dog gastrocnemius, the leg extensor for humans, and the traditional approach of humans performing two-legged exercise. The rat hindlimb is well suited for studying intense exercise with fast-twitch white fibers, but it is poorly suited for studying prolonged exercise because of rapid fatigue of major portions of the muscle and the restrictions of taking multiple blood samples. The traditional human model is limited because of the inability to quantify accurately the active muscle mass and to determine the true blood flow to the entire active tissue. Despite species differences and the various limitations of the paradigms, there are numerous consistencies in the literature. For example, human muscle and the canine gastrocnemius demonstrate similar magnitudes of efflux of ammonia, glutamine, and alanine (when indexed for the active mass) during prolonged exercise. Muscle has a large ammonia producing capacity during either intense or prolonged exercise. In prolonged exercise this is accompanied by similar productions of alanine and glutamine as well as a large uptake of glutamate. Despite the latter, the intramuscular glutamate concentration rapidly declines by more than 50% and remains constant throughout the exercise period. The leg extensor model and the canine gastrocnemius offer the greatest opportunities to quantify these responses during prolonged exercise.