Lung diffusing capacity (DL) for carbon monoxide (DLCO), nitric oxide (DLNO) or oxygen (DLO2) increases from rest to peak exercise without reaching an upper limit; this recruitment results from interactions among alveolar volume (VA), and cardiac output (q), as well as changing physical properties and spatial distribution of capillary erythrocytes, and is critical for maintaining a normal arterial oxygen saturation. DLCO and DLNO can be used to interpret the effectiveness of diffusive oxygen transport and track structural alterations of the alveolar-capillary barrier, providing sensitive noninvasive indicators of microvascular integrity in health and disease. Clinical interpretation of DL should take into account Q in addition to VA and hemoglobin concentration.