This review addresses three types of causes of respiratory system limitations to O2 transport and exercise performance that are experienced by significant numbers of active, highly fit younger and older adults. First, flow limitation in intrathoracic airways may occur during exercise because of narrowed, hyperactive airways or secondary to excessive ventilatory demands superimposed on a normal maximum flow-volume envelope. Narrowing of the extrathoracic, upper airway also occurs in some athletes at very high flow rates during heavy exercise. Examination of the breath-by-breath tidal flow-volume loop during exercise is key to a noninvasive diagnosis of flow limitation and to differentiation between intrathoracic and extrathoracic airway narrowing. Second exercise-induced arterial hypoxemia occurs secondary to an excessively widened alveolar-arterial oxygen pressure difference. This inefficient gas exchange may be attributable in part to small intracardiac or intrapulmonary shunts of deoxygenated mixed venous blood during exercise. The existence of these shunts at rest and during exercise may be determined by using saline solution contrast echocardiography. Finally, fatigue of the respiratory muscles resulting from sustained, high-intensity exercise and the resultant vasoconstrictor effects on limb muscle vasculature will also compromise O2 transport and performance. Exercise in the hypoxic environments of even moderately high alitudes will greatly exacerbate the negative influences of these respiratory system limitations to exercise performance, especially in highly fit individuals.