Maximal oxygen uptake (˙VO2max) is reduced in healthy individuals confined to bed rest, suggesting it is independent of any disease state. The magnitude of reduction in ˙VO2max is dependent on duration of bed rest and the initial level of aerobic fitness(˙VO2max), but it appears to be independent of age or gender. Bed rest induces an elevated maximal heart rate which, in turn, is associated with decreased cardiac vagal tone, increased sympathetic catecholamine secretion, and greater cardiac β-receptor sensitivity. Despite the elevation in heart rate, ˙VO2max is reduced primarily from decreased maximal stroke volume and cardiac output. An elevated ejection fraction during exercise following bed rest suggests that the lower stroke volume is not caused by ventricular dysfunction but is primarily the result of decreased venous return associated with lower circulating blood volume, reduced central venous pressure, and higher venous compliance in the lower extremities.˙VO2max, stroke volume, and cardiac output are further compromised by exercise in the upright posture. The contribution of hypovolemia to reduced cardiac output during exercise following bed rest is supported by the close relationship between the relative magnitude (%Δ) and time course of change in blood volume and ˙VO2max during bed rest, and also by the fact that retention of plasma volume is associated with maintenance of˙VO2max after bed rest. Arteriovenous oxygen difference during maximal exercise is not altered by bed rest, suggesting that peripheral mechanisms may not contribute significantly to the decreased˙VO2max. However, reduction in baseline and maximal muscle blood flow, red blood cell volume, and capillarization in working muscles represent peripheral mechanisms that may contribute to limited oxygen delivery and, subsequently, lowered ˙VO2max. Thus, alterations in cardiac and vascular functions induced by prolonged confinement to bed rest contribute to diminution of maximal oxygen uptake and reserve capacity to perform physical work.