The factors limiting force production and exercise endurance time have been briefly described, together with some of the changes occurring at various sites within the muscle and central nervous system. Evidence is presented that, in fatigue of sustained maximal voluntary contractions (MVC) executed by well-motivated subjects, the reduction in force generating capacity need not be due to a decline in central nervous system (CNS) motor drive or to failing neuromuscular transmission, but can be attributed solely to contractile failure of the muscles involved. However, despite this conclusion, both the integrated electromyogram (EMG) and the mean firing rate of individual motor units do decline progressively during sustained MVC. This, however, does not necessarily result in loss of force since the parallel slowing of muscle contractile speed reduces tetanic fusion frequency. It is suggested that the range of motoneuron firing rates elicited by voluntary effort is regulated and limited for each muscle to the minimum required for maximum force generation, thus preventing neuromuscular transmission failure and optimizing motor control. Such a CNS regulating mechanism would probably require some reflex feedback from the muscle.