As the first step in the oxygen-transport chain, the lung has a critical task: optimizing the exchange of respiratory gases to maintain delivery of oxygen and the elimination of carbon dioxide. In healthy subjects, gas exchange, as evaluated by the alveolar-to-arterial PO2 difference (A-aDO2), worsens with incremental exercise, and typically reaches an A-aDO2 of approximately 25 mmHg at peak exercise. While there is great individual variability, A-aDO2 is generally largest at peak exercise in subjects with the highest peak oxygen consumption. Inert gas data has shown that the increase in A-aDO2 is explained by decreased ventilation-perfusion matching, and the development of a diffusion limitation for oxygen. Gas exchange data does not indicate the presence of right-to-left intrapulmonary shunt developing with exercise, despite recent data suggesting that large-diameter arteriovenous shunt vessels may be recruited with exercise. At the same time, multisystem mechanisms regulate systemic acid-base balance in integrative processes that involve gas exchange between tissues and the environment and simultaneous net changes in the concentrations of strong and weak ions within, and transfer between, extracellular and intracellular fluids. The physicochemical approach to acid-base balance is used to understand the contributions from independent acid-base variables to measured acid-base disturbances within contracting skeletal muscle, erythrocytes and noncontracting tissues. In muscle, the magnitude of the disturbance is proportional to the concentrations of dissociated weak acids, the rate at which acid equivalents (strong acid) accumulate and the rate at which strong base cations are added to or removed from muscle. © 2013 American Physiological Society. Compr Physiol 3:693-739, 2013.