The sodium-hydrogen exchanger regulatory factors (NHERF-1 and NHERF-2) are a family of adaptor proteins characterized by the presence of two tandem PDZ protein interaction domains and a C-terminal domain that binds the cytoskeleton proteins ezrin, radixin, moesin, and merlin. The NHERF proteins are highly expressed in the kidney, small intestine, and other organs, where they associate with a number of transporters and ion channels, signaling proteins, and transcription factors. Recent evidence has revealed important associations between the NHERF proteins and several G protein-coupled receptors such as the beta2-adrenergic receptor, the kappa-opioid receptor, and the parathyroid hormone receptor, as well as growth factor tyrosine kinase receptors such as the platelet-derived growth factor receptor and the epidermal growth factor receptor. This review summarizes the emerging data on the biochemical mechanisms, physiologic outcomes, and potential clinical implications of the assembly and disassembly of receptor/NHERF complexes.