It has always been of great interest for scientists to study human performance and fatigue in order to better understand the limiting factors and detenninants, which ultimately rule exercise tolerance in humans. In the last decades, the focus has moved to study fatigue and human performance not only from a physiological point of view but also to integrate it with psychophysiological mechanisms in order to reach a fuller understanding of fatigue processes and its implications on exercise performance. The aim of this thesis was to analyse the most prominent models of exercise tolerance and delineate psychological and physiological factors determining and/or limiting exercise perfonnance. Moreover, the role of "effort" and its implications for exercise tolerance has been defined and elucidated. In chapter 2, it has been shown that maximal voluntary cycling power measured before and immediately after exhaustive cycling exercise does not decrease below the constant power at which participants were cycling at exhaustion. Such decrease in power, therefore, does not explain and challenge the traditional assumptions that in high intensity aerobic exercise muscle fatigue causes exhaustion, which occurs when the power generated from the muscles does not match any longer the power required by the task. Moreover, this study suggests the implication of other psychobiological variables such as rating of perceived exertion as important detenninant and main limiting factor of exercise tolerance In chapter 3 has been tested the hypothesis that rating of perceived exertion and naturally occuning muscle pain, the two main perceptual detenninants influencing physical performance have a different impact on physical performance. Muscle pain unpleasantness (Cook's scale) and rating of perceived exertion (RPE) (Borg's scale) were rated during a high intensity aerobic cycling test. During the cycling task, a constant increase in RPE was reported until subjects withdrew exercise while naturally occurring muscle pain rating increased at a moderate level without reaching the maximal rating. These findings suggest a high c01Telation between rating of perceived exertion and high intensity cycling at exhaustion and minimize the impact of naturally occurring muscle pain as limiting factor in aerobic perfonnance. In chapter 4 it has been tested the validity and efficacy of a novel protocol to measure neural c01Telates of rating of perceived exertion using functional magnetic resonance imaging (fMRI). By comparing two different conditions: Fatigued leg vs. Non fatigued Leg, nine participants perfonned a series of leg extensions tasks alternating both legs. During this task, brain activation was measured using a 3 Tesla fMRI scanner and rating of perceived exertion has been recorded. Main results have shown an increase in rating of perceived exertion concomitantly to an increase in central motor command across the series of leg extension task perfom1ed and a significant activation of the cingulate gyrus and insular cortex has been detected when comparing higher ratings of effort compared to lower ones. These new findings may help the understanding of the neurobiology of perceived exertion and the brain areas and neural processes implicated with an increase of the rating of perceived exertion. Moreover, it elucidates the role of effort-based decision-making mechanisms related with perceived exertion. Overall, our findings showed the validity of a more psychophysiological approach to study complex processes of fatigue and to delineate main determinants involved in human perfonnance with particular attention to the rating of perceived exertion. It redefined the role and the impact of exercise-related muscle pain in endurance perfo1mance. Finally, it proposes new neurophysiological insights into the origin and development of perceptions of effort in the brain.