A system mediating the exchange of Na+ for H+ appears to be present in most, if not all, animal cells. It was originally described in the brush border membrane of intestinal and renal epithelial cells. 1 In the epithelium, the antiport is believed to play a role in transepithelial transport 2 and as a mediator of transcellular “cross-talk”. 3 , 4 In unstimulated nonepithelial cell types the exchanger is thought to be more or less quiescent when the cytoplasmic pH (pHi) is in the physiological range and becomes activated at a lower pHi. Thus, it is considered as a mechanism involved in pHi regulation. This exchanger can, however, be stimulated by a variety of stimuli other than pHi, including hormones, growth factors, tumor promoters, and hypertonic shrinking. 5 These agents induce an alkaline shift of the pHi dependence of the antiport and as a result the quiescent exchanger becomes activated at a normal pHi. The different biological effects resulting from such stimulations (cell volume regulation and initiation of cell proliferation) are believed to be mediated by activation of protein kinases, and it is supposed that agonist-induced protein phosphorylation is required for the shift in pHi dependence. Very few examples of phosphorylation and/or modulation of the Na+/H+ antiport by cAMP have been reported. The few reported instances fall into two distinct groups: (1) those obtained in epithelia in which the rate of Na+/H+ exchange was shown to be reduced by elevating the cytoplasmic levels of cAMP and (2) those obtained in some nucleated red blood cells showing a cAMP activation of the exchanger. It is noteworthy that, by comparison with the other previously described exchangers, the cAMP-activated Na+/H+ antiporter observed in erythrocytes seems to possess particular characteristics concerning both certain of its control mechanisms and its putative physiological role.