Muscle fatigue encompasses a class of acute effects that impair motor performance. The mechanisms that can produce fatigue involve all elements of the motor system, from a failure of the formulation of the descending drive provided by suprasegmental centers to a reduction in the activity of the contractile proteins. We propose four themes that provide a basis for the systematic evaluation of the neural and neuromuscular fatigue mechanisms: 1) task dependency to identify the conditions that activate the various mechanisms; 2) force-fatigability relationship to explore the interaction between the mechanisms that results in a hyperbolic relationship between force and endurance time; 3) muscle wisdom to examine the association among a concurrent decline in force, relaxation rate, and motor neuron discharge that results in an optimization of force; and 4) sense of effort to determine the role of effort in the impairment of performance. On the basis of this perspective with an emphasis on neural mechanisms, we suggest a number of experiments to advance our understanding of the neurobiology of muscle fatigue.