[Truncated abstract] A reduction in the force-generating capacity of a muscle is the primary indicator of fatigue and the majority of this force loss is the result of peripheral fatigue. However, there is also evidence that the central nervous system (CNS) does not drive muscles maximally during fatiguing exercise, which has led to the concept of central fatigue. The strongest evidence for this comes from interpolated twitch studies showing that transcranial magnetic stimulation (TMS) during a maximal voluntary contraction can produce an increment in force which becomes greater as fatigue develops. In addition, the silent period (SP) duration increases during a fatiguing exercise, suggesting that there is a buildup of intracortical inhibition that might limit central motor drive. In contrast, motor evoked potential (MEP) amplitude increases during fatigue suggesting an increase in corticomotor excitability during exercise . . . The primary finding was a progressive increase in the fMRI signal during exercise, with a reduction following exercise, and signal changes were observed in all regions. These studies provide evidence that central adaptive processes occur during muscle fatigue and highlight the potential to facilitate these processes with interventional paradigms. The findings indicate the extent of cortical changes during fatigue and suggest that there may also be neurohaemodynamic and/or metabolic components to central adaptive processes. Understanding the central response to muscle fatigue should incorporate mechanisms both of central adaptation and central fatigue.