Throughout their evolution, mammalian hemoglobins have acquired a broad repertoire of functional properties well suited to the internal milieu of the red cell. Mammals display a wide range in whole blood oxygen affinity dependent on three major factors: the intrinsic oxygen affinity of the hemoglobin, the level of red cell 2,3-DPG, and the response of the hemoglobin to 2,3-DPG. The concentration of 2,3-DPG varies among groups of mammals. Those animals (cats and ruminants) that have very low levels of this intracellular mediator have hemoglobins of intrinsically low oxygen affinity that fail to respond to the addition of 2,3-DPG. Mammals that have adapted to various types of hypoxia tend to have increased oxygen affinity, primarily mediated through reduced levels of red cell 2,3-DPG. In contrast, mammals who are experimentally subjected to low oxygen tensions develop decreased oxygen affinity owing to increased red cell 2,3-DPG. Mammals employ one of three different mechanisms for the maintenance of higher oxygen affinity of fetal red cells, compared to maternal red cells. Many of these phenomena can be satisfactorily explained at the molecular level but their adaptational significance is less clear.