The concept that underlies this paper is that carbon dioxide (CO2) removal is at least as important as the delivery of oxygen for maximum performance during exercise. Increases in CO2pressure and reductions in the pH of muscle influence muscle contractile properties and muscle metabolism (via effects on rate-limiting enzymes), and contribute to limiting symptoms. The approach of Barcroft exemplified the importance of integrative physiology, in describing the adaptive responses of the circulatory and respiratory systems to the demands of CO2production during exercise. The extent to which failure in the response of one system may be countered by adaptation in another is also explained by this approach. A key factor in these linked systems is the transport of CO2in the circulation. CO2is mainly (90%) transported as bicarbonate ions — as such, transport of CO2is critically related to acid–base homeostasis. Understanding in this field has been facilitated by the approach of Peter Stewart. Rooted in classical physico–chemical relationships, the approach identifies the independent variables contributing to homeostasis — the strong ion difference ([SID]), ionization of weak acids (buffers, Atot) and CO2pressure (PCO2). The independent variables may be reliably measured or estimated in muscle, plasma, and whole blood. Equilibrium conditions are calculated to derive the dependent variables — the most important being the concentrations of bicarbonate and hydrogen ions. During heavy exercise, muscle [H+] can exceed 300 nEq·L–1(pH 6.5), mainly due to a greatly elevated PCO2and fall in [SID] as a result of increased lactate (La–) production. As blood flows through active muscle, [La–] increase in plasma is reduced by uptake of La–and Cl–by red blood cells, with a resultant increase in plasma [HCO3–]. Inactive muscle contributes to homeostasis through transfer of La–and Cl–into the muscle from both plasma and red blood cells; this results in a large increase in [HCO3–]. In the lungs, oxygenation of hemoglobin increases red blood cell [A–] aiding rapid conversion of HCO3–into CO2in red cells (containing carbonic anhydrase), with diffusion of CO2into alveoli, but full equilibration of the CO2system in plasma may not occur during the short pulmonary capillary circulation time in heavy exercise. The ionization state of imidazole groups on protein histidine may provide integration between acid–base homeostasis, membrane anion transfer proteins, and activation of rate-limiting enzymes.