Locomotor muscle fatigue develops during endurance events and it is traditionally thought to limit performance despite no direct experimental evidence in favour of this hypothesis. Similarly, muscle damage is known to limiting strength and power performance, but there was no evidence that it can reduce endurance exercise performance. The aims of this thesis are to investigate the effects of locomotor muscle fatigue and damage on endurance performance and the physiological and perceptual response to exercise. In the first study, we tested the hypothesis that exercise-induced muscle damage can decrease performance during a 30 min running time trial. A significant relative 4%decrease in running performance was showed in subjects with exercise-induced muscle damage. In the second study locomotor muscle fatigue was induced with an eccentric exercise protocol to test its detrimental effect on time to exhaustion during high-intensity constant-power cycling independently of metabolic stress. A significant 15% drop in lower limb strength (compared to baseline) determined a shortening of the time to exhaustion from 750 ± 281 s to 636 ± 278 s. The third study provides a more in depth analysis of the effects of reduced locomotor muscle force per se on the physiological and perceptual response to high intensity endurance exercise. Locomotor muscle fatigue entailed an increase in heart rate, breathing frequency, and perceived exertion despite no change in the metabolic requirements. The same exercise protocol was used in the fourth study to investigate effects of locomotor muscle fatigue on incremental exercise performance and physiological/perceptual responses during cycling at di fferent intensities. Although no changes occurred in the physiological responses to incremental exercise, the 13% decrease in locomotor muscle force determined a 2% decrease in the peak power output (an overall difference of 21 W ) and a significant increase in the perceived leg effort. Overall, our findings show that both locomotor muscle fatigue and damage significantly and reliably impair endurance exercise performance between 10 and 30 minutes. However, the effects of increased central motor command to weaker locomotor muscles on cardiorespiratory responses seem to be dependent upon the degree of strength loss and the intensity of exercise. Finally, perception of effort is augmented by locomotor muscle fatigue and damage, and provides the most plausible explanation for the curtailment of endurance performance.