Existing evidence suggests that exercise-induced alterations of the metabolic milieu of locomotor muscle and associated peripheral muscle fatigue affect the central projection of thin-fiber muscle afferents. These neurons provide inhibitory feedback to the CNS and thereby influence the magnitude of central motor drive during high-intensity whole-body endurance exercise. The purpose of this proposed feedback loop would be to regulate and restrict the development of exercise-induced peripheral muscle fatigue and/or associated sensory feedback to an "individual critical threshold." This centrally mediated restriction in the development of peripheral locomotor muscle fatigue might thereby help to prevent excessive disturbance of muscle homeostasis and potential harm to the organism. It seems that the regulatory mechanism is dominant during exercise under "normal" conditions but might become secondary in the face of extreme environmental influences such as severe hypoxia or heat. Most recent data are used to emphasize how the proposed feedback loop might be a key factor limiting performance during high-intensity whole-body endurance exercise.