Na+/H+ exchangers (NHEs) extrude protons from, and take up sodium ions into cells. Six isoforms, NHE-1 - NHE-6, have been cloned. NHE proteins are composed of an N-terminal domain, which most likely crosses the cell membrane 12 times and constitutes the cation exchange machinery, and a C-terminal tail, which modulates the exchanger by interacting with protein kinases and regulatory factors. The "house-keeping" NHE-1 is located at the basolateral membrane of most renal tubule cells; NHE-2 is located apically in selected nephron segments. As suggested from data with NHE-1 and NHE-2 deficient mice, both isoforms play a minor role in renal salt and water handling. NHE-3 is located at the apical membrane of proximal tubule and thick ascending limb cells, is involved in Na+ absorption, and is responsible for the majority of bicarbonate absorption. NHE-3 is modulated by the NHE regulating factor, which interacts with further proteins, protein kinases, and the cytoskeleton. Downregulation of NHE-3 by parathyroid hormone, dopamine, and by an increase in blood pressure leads to saluresis/diuresis. The failure of dopamine to downregulate NHE-3 may cause hypertension through renal salt and water retention. NHE-3 knockouts are hypotonic and can not survive on low salt diet. In chronic acidosis, NHE-3 is upregulated possibly through increased local endothelin production. NHE4 has been found mostly in renal medulla. The precise function of this isoform, which is activated by hypertonicity and can perform K+/H+ exchange, is not clear. The segmental location and function of NHE-5 and NHE-6 in the kidney are unknown at present.