Our understanding of the mechanisms of diseases that result in impaired functional capacity, and impair an individual’s ability to work, recreate, and perform activities of daily living, has evolved in a remarkable and surprising manner. In the past, we knew that a patient with heart failure had dyspnea and fatigue because the heart pumped insufficient blood and the lungs became congested. Similarly, we knew that lung disease limited patients because their ability to increase ventilation was inadequate to meet the increased metabolic demands of work. Of course, newer explanations have challenged many of these ideas, largely because reduced function of the primarily involved organ frequently fails to account for the magnitude of reduction in overall capacity (eg, decreased maximum oxygen uptake [V̇o2]). Decreased left ventricular ejection fraction, cardiac output, and stroke volume in patients with chronic heart failure, for example, do not entirely explain reduced exercise capacity and poorer prognosis. Accordingly, other contributing factors have been sought and identified, including abnormalities of the peripheral circulation, muscles of ambulation, lungs, and the pulmonary circulation.