The purpose of this review is to acquaint the reader with the neurobiology of muscle fatigue. Muscle fatigue is a complex, multifactorial process. The authors have covered the chain of events bringing about skeletal muscle contraction and the manner in which fatigue may affect each step. Advances in technology continue to increase understanding of central fatigue. Many excellent studies of peripheral fatigue have been designed to delineate the mechanisms that influence the excitation-contraction coupling, energy supply, and force generation processes. Although much of this work has considered mechanisms in isolation, different mechanisms may be responsible under different conditions. Fatigue is a common complaint among patients with a variety of neuromuscular and metabolic diseases. Armed with an enhanced knowledge of the mechanisms of muscle fatigue, one can more fully recognize the signs and symptoms of metabolic disorders and neuromuscular diseases and use diagnostic testing. The clinician should anticipate the role of muscle fatigue in injury and focus on injury prevention strategies, especially during the restorative phase of rehabilitation. As a clinician-scientist concerned with optimizing patients' and athletes' performance, one must design ways to identify, measure, and treat muscle fatigue. Beyond illustrating what is currently known about muscle fatigue, the authors hope this review inspires the reader to solve problems of great clinical importance to patients and athletes alike.