The duration that exercise can be maintained decreases as the power requirements increase. In this review, we describe the power–duration (PD) relationship across the full range of attainable power outputs in humans. We show that a remarkably small range of power outputs is sustainable (power outputs below the critical power, CP). We also show that the origin of neuromuscular fatigue differs considerably depending on the exercise intensity domain in which exercise is performed. In the moderate domain (below the lactate threshold, LT), fatigue develops slowly and is predominantly of central origin (residing in the central nervous system). In the heavy domain (above LT but below CP), both central and peripheral (muscle) fatigue are observed. In this domain, fatigue is frequently correlated with the depletion of muscle glycogen. Severe-intensity exercise (above the CP) is associated with progressive derangements of muscle metabolic homeostasis and consequent peripheral fatigue. To counter these effects, muscle activity increases progressively, as does pulmonary oxygen uptake (
), with task failure being associated with the attainment of
max. Although the loss of homeostasis and thus fatigue develop more rapidly the higher the power output is above CP, the metabolic disturbance and the degree of peripheral fatigue reach similar values at task failure. We provide evidence that the failure to continue severe-intensity exercise is a physiological phenomenon involving multiple interacting mechanisms which indicate a mismatch between neuromuscular power demand and instantaneous power supply. Valid integrative models of fatigue must account for the PD relationship and its physiological basis.