The discovery of the S-shaped O2 equilibrium curve and the Bohr effect in 1904 stimulated a fertile and continued research into respiratory functions of blood and allosteric mechanisms in haemoglobin (Hb). The Bohr effect (influence of pH/CO2 on Hb O2 affinity) and the reciprocal Haldane effect (influence of HbO2 saturation on H+/CO2 binding) originate in the Hb oxy-deoxy conformational change and allosteric interactions between O2 and H+/CO2 binding sites. In steady state, H+ is passively distributed across the vertebrate red blood cell (RBC) membrane, and intracellular pH (pHi) changes are related to changes in extracellular pH, Hb-O2 saturation and RBC organic phosphate content. As the Hb molecule shifts between the oxy and deoxy conformation in arterial-venous gas transport, it delivers O2 and takes up CO2 and H+ in tissue capillaries (elegantly aided by the Bohr effect). Concomitantly, the RBC may sense local O2 demand via the degree of Hb deoxygenation and release vasodilatory agents to match local blood flow with requirements. Three recent hypotheses suggest (1) release of NO from S-nitroso-Hb upon deoxygenation, (2) reduction of nitrite to vasoactive NO by deoxy haems, and (3) release of ATP. Inside RBCs, carbonic anhydrase (CA) provides fast hydration of metabolic CO2 and ensures that the Bohr shift occurs during capillary transit. The formed H+ is bound to Hb (Haldane effect) while HCO3- is shifted to plasma via the anion exchanger (AE1). The magnitude of the oxylabile H+ binding shows characteristic differences among vertebrates. Alternative strategies for CO2 transport include direct HCO3- binding to deoxyHb in crocodilians, and high intracellular free [HCO3-] (due to high pHi) in lampreys. At the RBC membrane, CA, AE1 and other proteins may associate into what appears to be an integrated gas exchange metabolon. Oxygenation-linked binding of Hb to the membrane may regulate glycolysis in mammals and perhaps also oxygen-sensitive ion transport involved in RBC volume and pHi regulation. Blood O2 transport shows several adaptive changes during exposure to environmental hypoxia. The Bohr effect is involved via the respiratory alkalosis induced by hyperventilation, and also via the pHi change that results from modulation of RBC organic phosphate content. In teleost fish, beta-adrenergic activation of Na+/H+ exchange rapidly elevates pHi and O2 affinity, particularly under low O2 conditions.