There is substantial evidence that fatiguing exercise is accompanied by changes within the central nervous system that reduce the force that can be produced by working muscles. Here we review studies that used non-invasive neurophysiological techniques to show that sustained single-joint contractions have the capacity to increase corticospinal responsiveness and reduce motoneuronal responsiveness. We contrast these findings with new evidence from our laboratory regarding corticospinal responsiveness during sustained cycling exercise. There seems to be a similar increase in responsiveness of the intracortical inhibitory interneurons during sustained locomotor and single-joint exercise which might be due to acute exercise responses that are common to fatiguing exercise of any nature, such as local accumulation of fatigue metabolites. In contrast, the pattern of changes in corticospinal responsiveness is fundamentally different between the two modes of exercise which might be due to greater systemic fatigue responses to locomotor exercises.