The reduction in maximal oxygen consumption in hypoxia can be due to physiological factors, the relative importance of which depends on the degree of hypoxia: the reduction in inspired PO2, the impairment of lung gas exchange contributing to an exercise-induced decrease in arterial O(2) saturation, the reduction in maximal cardiac output and the limitation in tissue diffusion. This paper focuses on two aspects of this oxygen cascade. First, the decrease in heart rate at maximal exercise in prolonged exposure to hypoxia is discussed and the role of changes in the autonomous nervous system is emphasised. The desensitization of the beta-adrenergic pathway and the upregulation of the muscarinic pathway, both using G-protein systems, contribute to limit the myocardial O(2) consumption in face of reduced O(2) availability during maximal exercise in hypoxia. The changes in O(2) diffusion to the tissues are discussed in relation to the expression of hypoxia inducible factor (HIF-1alpha) and vascular endothelial growth factor (VEGF) and their possible changes induced by training and/or hypoxic exposure.