This brief review summarizes progress that has been made in the study of muscle fatigue since a review published 15 years ago (Enoka RM, Stuart DG. 1992. Neurobiology of muscle fatigue. J Appl Physiol 72:1631-48.). The present review first discusses progress on the four themes identified in the 1992 review and then describes a new approach that can be used to identify the functionally significant physiological adjustments that occur during fatiguing contractions. As described in the previous review, it is currently not possible to develop a comprehensive model of muscle fatigue because the prevailing mechanism that impairs performance varies with the characteristics of the task that is being performed. An alternative approach is to focus on the mechanisms that cause failure to complete the task. This task-failure approach involves comparing two performances and identifying the adjustments that limit the rate for the more difficult condition. With this approach, initial studies have demonstrated that the time to failure of a sustained contraction can be influenced by such variables as the type of load supported by the limb, the posture of the limb, and the group of muscles involved in the task. The challenge is to identify the mechanisms that enable these different variables influence the time to task failure.