Reduced oxygen supply to contracting muscles affects not only the metabolic paths but also modifies the gain of sensorimotor reflex loops initiated from the activation of specialized nervous endings that detect the changes in muscle metabolism and membrane outflow of potassium. Large differences are found between skeletal muscles and the diaphragm with respect to their sensitivity to acute or chronic hypoxia. The diaphragm tolerates much more hypoxemia than do skeletal muscles, namely those constituted by a large proportion of slow twitch oxidative fibers. Acute hypoxemia or ischemia accentuates the inhibitory influences exerted by the afferent paths from muscle metaboreceptors. This adaptative response may be responsible for enhanced muscle wisdom phenomenon during fatiguing contractions under hypoxic conditions. Prolonged and severe chronic hypoxemia markedly reduces muscle force generation by skeletal muscles and their endurance to fatigue. Restoration of normal PaO2 levels in these individuals immediately improves maximal muscle performance, perhaps through more efficient excitation-contraction coupling. Recent data on the consequences of hypoxia on muscle metabolism and the associated changes in sensorimotor control strongly suggest that local acidosis cannot entirely explain all electromyogram changes found during and after fatiguing exercise.