The activity of the sodium/hydrogen exchanger 3 (NHE3) isoform of the sodium/hydrogen exchanger in the brush-border membrane of the renal proximal tubule is tightly regulated. Recent biochemical and cellular experiments have established the essential requirement for a new class of regulatory factors, sodium/hydrogen exchanger regulatory factor (NHERF) and NHERF-like proteins, in cAMP-mediated inhibition of NHE3 activity. NHERF is the first PSD-95/Dlg/ZO-1 (PDZ) motif-containing protein localized to apical membranes and appears to facilitate cAMP-dependent protein kinase A (PKA) phosphorylation of NHE3 by interacting with the cytoskeleton to target a multiprotein complex to the brush-border membrane. Other recent experiments have indicated that NHERF also regulates the activity of other renal transport proteins, suggesting that the signal complex model of signal transduction in the kidney may be more common than presently appreciated. This article reviews studies on the regulation of NHE3 by NHERF, PKA, and ezrin and introduces the concept of regulation of renal transporters by signal complexes. Although not the primary focus of this review, recent studies have indicated a role for NHERF in membrane targeting, trafficking, and sorting of transporters, receptors, and signaling proteins. Thus NHERF and related PDZ-containing proteins appear to be essential adapters for regulation of renal transporters in the mammalian kidney that maintain salt and water balance.