The Na(+)-H+ exchanger is a ubiquitous transport system that is involved in the regulation of intracellular pH, cell growth and proliferation, cell volume regulation, and transepithelial absorption of Na+, Cl-, and HCO3-. Altered activity of the Na(+)-H+ exchanger has been implicated as a mechanism contributing to the development of high blood pressure in subgroups of patients with essential hypertension and in various animal models of hypertension. Many of these studies measured Na(+)-Li+ exchange rather than Na(+)-H+ exchange, hypothesizing that Na(+)-Li+ exchange represents a functional mode of the Na(+)-H+ exchanger. However, this is a controversial assumption. Several studies have also shown an association between erythrocyte Na(+)-Li(+)-exchange rate and predisposition to nephropathy in patients with insulin-dependent diabetes mellitus. The recent cDNA cloning of at least one isoform of the Na(+)-H+ exchanger will help clarify the cellular mechanisms of regulation of the exchanger and its possible role in pathophysiological states such as hypertension.