It is well established that altering O₂ delivery to contracting skeletal muscle affects human performance. In this respect, a reduced O₂ supply (e.g., hypoxia) increases the rate of muscle fatigue, whereas increasing O₂ supply (e.g., hyperoxia) reduces the rate of fatigue. Interestingly, the faster onset of fatigue in moderate hypoxia does not appear to be a consequence of mitochondrial O₂ limitation because these effects occur at submaximal rates of O₂ consumption for these conditions and at O₂ tensions well above that which impairs mitochondrial O₂ uptake in vitro. Alterations in O₂ supply modulate the regulation of cellular respiration and may affect the onset of impaired Ca²⁺ handling with fatigue. Specifically, changes in O₂ supply alter the coupling between phosphocreatine hydrolysis and O₂ uptake in contracting muscles, which by determining the rate of inorganic phosphate (Pi) accumulation may affect Ca²⁺ release. Partial ischemia differs somewhat in that the reduction in force could be due to reduced O₂ supply and/or impaired removal of metabolic by-products secondary to insufficient blood flow. Nonetheless, recent evidence shows a parallel decline and restoration of force with alterations in O₂ supply but not blood flow alone during submaximal contractions. Furthermore, the causes of fatigue are similar when O₂ is plentiful and when it is reduced. Key words: muscular contractions, aerobic performance, hypoxia, hyperoxia, muscle bioenergetic