Hemoglobin (Hb) constitutes a vital link between ambient O
2
availability and aerobic metabolism by transporting oxygen (O
2
) from the respiratory surfaces of the lungs or gills to the O
2
‐consuming tissues. The amount of O
2
available to tissues depends on the blood‐perfusion rate, as well as the arterio‐venous difference in blood O
2
contents, which is determined by the respective loading and unloading O
2
tensions and Hb‐O
2
‐affinity. S
hort‐term
adjustments in tissue oxygen delivery in response to decreased O
2
supply or increased O
2
demand (under exercise, hypoxia at high altitude, cardiovascular disease, and ischemia) are mediated by metabolically induced changes in the red cell levels of allosteric effectors such as protons (H
+
), carbon dioxide (CO
2
), organic phosphates, and chloride (Cl
−
) that modulate Hb‐O
2
affinity. The
long‐term
, genetically coded adaptations in oxygen transport encountered in animals that permanently are subjected to low environmental O
2
tensions commonly result from changes in the molecular structure of Hb, notably amino acid exchanges that alter Hb's intrinsic O
2
affinity or its sensitivity to allosteric effectors. Structure‐function studies of animal Hbs and human Hb mutants illustrate the different strategies for adjusting Hb‐O
2
affinity and optimizing tissue oxygen supply. © 2012 American Physiological Society.
Compr Physiol
2:1463‐1489, 2012.