Starting from observations in intact cells and extending to studies in native membranes and solubilized membrane proteins, a significant body of evidence has been accumulated to indicate that some of the short-term regulatory influences on the Na+-H+ exchanger in the apical membrane of the proximal convoluted tubule act via protein phosphorylation mediated by specific protein kinases. Protein phosphorylation mediated by PKA inhibits the Na+-H+ exchanger while that mediated by PKC stimulates activity. The effect of PKA and PKC on the Na+-H+ exchanger in native membranes and in solubilized brush border membrane proteins appears to be consistent with most of the published observations in intact cells. Further studies using solubilized, renal brush border membrane proteins indicated that protein phosphorylation mediated by CaM-kinase II inhibited the activity of the Na+-H+ exchanger. The physiologic significance of this observation in intact cells remains to be determined. It is hoped that the types of experimental approaches outlined in this review will yield additional insights into the structure of the Na+-H+ exchanger and to a clearer understanding of its physiologic regulation.