The principal function of the heart is to maintain O₂ delivery by regulating cardiac output (Q). The lower atmospheric pO₂ at altitude and subsequent arterial hypoxemia reduces the arterial oxygen content (CaO₂). At rest and during submaximal exercise in acute hypoxia, systemic O₂ delivery is maintained at sea level values by rising the cardiac output through increasing heart rate (HR), while stroke volume (SV) remains at the same level as in normoxia, implying increased venous return during hypoxia. The increase in HR results from elevated sympathetic activity and parasympathetic withdrawal. Despite a linear reduction of exercise maximal HR (HRmax) with altitude, maximal cardiac output (Qmax) is preserved up to 4000-4500 m. In severe acute hypoxia, Qmax may reach slightly lower values than normoxia, compromising systemic O₂ delivery. Sympathetic activation is proportional to the level of hypoxemia and is necessary to counteract the hypotensive effects of hypoxia. With acclimatisation, CaO₂ is increased to values similar to or above those observed at sea level, and resting at submaximal exercise Qs are similar to those seen before acclimatisation. However, Qmax is 20-30% lower in chronic hypoxia than at sea level. Since the relative reduction of Qmax exceeds the relative increase of CaO₂, maximal exercise systemic O₂ delivery is reduced in chronic hypoxia, and hence VO₂max. The reduction in Qmax is associated with a marked decrease in HRmax due to vagal overactivity. Experiments in chronic hypoxia have shown that increasing HRmax to the normoxic values by pharmacologically blocking the muscarinic receptors with glycopyrrolate does not affect Qmax due to a proportional reduction of SV, leaving VO₂max and peak power output unchanged. Chronic hypoxia is accompanied by sympathetic overactivity at rest and during exercise, resulting in higher blood pressure. However, lowering the afterload by reducing blood viscosity through isovolumic haemodilution or peripheral vasodilation (infusion of ATP into one femoral artery at peak exercise) had almost no influence on Qmax. Although blood volume is reduced during the first 1-3 months of residence at altitude, plasma volume expansion (+ 1 litre of 6% dextran) does not significantly impact Qmax. The fact that sea level Qmax can be achieved in chronic hypoxia with moderate hyperoxia indicates that the limiting factor is regulatory and not structural (i.e., due to changes at the level of the myocardium). Additionally, it has been suggested that Qmax may be reduced in severe hypoxia through: i) reduced SV due to an increased right heart afterload caused by hypoxic pulmonary hypertension, ii) impaired diastolic function, iii) a direct negative inotropic effect of hypoxia, and iv) central mechanisms (attenuated central command and reduced activation of vasomotor centres). The regulatory mechanisms by which chronic hypoxia blunts Qmax remain essentially unknown.