The epithelial brush border Na/H exchanger NHE3 accounts for the majority of intestinal and renal Na absorption. It is part of the neutral NaCl absorptive process in which it is linked to a member of the SLC26A gene family, either DRA or PAT-1. This protein is highly regulated being initially inhibited in the post-prandial state and then stimulated. Most of the regulation occurs via changes in trafficking although changes in turnover number occur as well. NHE3 has two domains, a N-terminal 455 aa transport domain and a 377 aa C-terminal, intracellular regulatory domain. The structure of the transport domain has not been solved but appears to be the same as that of the bacterial Na/H antiporter, NhaA. The C-terminal regulatory domain binds NHE3 to the cytoskeleton at two sites, a more N-terminal site at which ezrin directly binds NHE3 to the actin cytoskeleton and a more C-terminal site at which ezrin indirectly binds NHE3 via attachment to the multiple PDZ domain containing proteins NHERF1 and NHERF2. Under basal conditions, NHE3 is fixed to the cytoskeleton which requires NHERF binding. However, with signaling that increases endocytosis or exocytosis of NHE3, NHE3 is transiently freed from the cytoskeletal attachment to the NHERFs which allows trafficking along the microvillus. The NHE3 C-terminal acts as a scaffold, forming complexes with its regulatory proteins to create a platform involved in its regulation. At the sites of the two areas of cytoskeletal attachment, NHE3 forms large signaling complexes that cause NHE3 to appear in complexes up to 1200 kDA. These complexes are dynamic and change with signaling with some proteins being added and others removed from the NHE3 C-terminal as part of acute regulation. The complexes formed at the site of the attachment to the cytoskeleton appear to have separate functions in NHE3 regulation. The NHERF binding domain also binds CaM KII, CaM, CK2, PLCg and is involved in complex formation. The direct ezrin binding domain is needed for all aspects of NHE3 trafficking. The dynamic aspects of NHE3 complex formation may be a model for complex formation in regulation of many transport proteins.