By virtue of their electroneutral exchange of intracellular H+ for extracellular Na+, the Na+/H+ exchangers (NHE1-NHE8) play a pivotal role in many physiological processes. This review focuses on the ubiquitous plasma membrane isoform, NHE1. Particular attention is given to the roles and regulation of NHE1 in erythrocytes, in their own right and as model systems, but pertinent findings from non-erythroid cells are also discussed. NHE1 plays a key role in the regulation of cell volume and pH, and consequently in the control of such diverse processes as blood O2/CO2 transport, and cell proliferation, motility, and survival. Disturbances in NHE1 function are involved in important pathological states such as hypoxic cell damage and cancer development. NHE1 has a predicted topology of 12 transmembrane domains, and a hydrophilic C-terminus thought to be the major site for NHE1 regulation. NHE1 is highly conserved throughout the vertebrate phylum, particularly in the transmembrane region and the proximal part of the C-terminus. In non-erythroid, and probably also in erythroid cells, this part of the hydrophilic C-terminus interacts with multiple binding partners important for NHE1 function. Erythrocyte NHE1s from mammalian, amphibian, and teleost species are activated by cell shrinkage, decreased pH(i), inhibition of Ser/Thr protein phosphatases, and activation of Ser/Thr protein kinases, i.e., many of the stimuli activating NHE1 in non-erythroid cells. In erythrocytes of many lower vertebrates, NHE1 is activated during hypoxia and is an important modulator of hemoglobin oxygen affinity. Sensitivity of NHE1 to oxygenation status has recently been described also in non-erythroid mammalian cells.