The Na+/H+ exchangers (NHE) are a ubiquitous family of membrane proteins that catalyze the counter-transport of extracellular Na+ for intracellular H+ and are important for intracellular pH and cell volume regulation. The major epithelial isoforms, NHE2 and NHE3, are thought to have more specialized roles in regulating Na+ and water absorption and are differentially expressed in epithelial tissues. NHE2 and NHE3 not only differ with respect to their response to various endogenous and exogenous factors but exhibit different intracellular localization as well. NHE2 is primarily located at the plasma membrane, whereas NHE3 is mostly sequestered in an intracellular compartment corresponding to the recycling endosome. Furthermore, NHE3 is localized to the apical pole, whereas polar localization of NHE2 has been controversial. The author has recently localized NHE2 to the apical membrane of a renal epithelial cell line and identified a 45-residue-long region of the cytosolic domain (corresponding to residues 731-777 of the rat NHE2) to be critical for apical targeting. Although SH3 domains of various proteins were found to bind to this and a more carboxy-terminal proline-rich region in vitro, the functional significance of these interactions appears inconsequential. Deletion of both proline-rich regions did not affect Na+/H+ exchange nor its response to hypertonicity and metabolic depletion. However, loss of residues 731-777, which bound specifically in vitro to the SH3 domain of the cytoskeletal protein, alpha-spectrin, mistargets NHE2 to the basolateral surface.