In the gastrointestinal tract, CFTR, in conjunction with one or several members of the SLC26 anion exchanger family, mediates electrogenic Cl- and HCO3- secretion. Na+/H+ exchanger isoform NHE3, on the other hand, coupled to one or several of the SLC26 isoforms, mediates electroneutral NaCl absorption. The agonist-induced activation of anion secretion and inhibition of salt absorption causes secretory diarrhea. Current dogma sees the formation of a multiprotein complex of transport proteins, postsynaptic density-95/discs large/zonula occludens-1 (PDZ) adapter proteins, anchoring proteins, the cytoskeleton, and the involved protein kinases as one crucial step in the regulation of these transport processes. Data obtained in heterologous expression studies suggest an important role of these PDZ adapter proteins in trafficking, endocytic recycling, and membrane retention of the respective transmembrane proteins. This article reviews recent advances in our understanding of the role of the PDZ adapter proteins NHERF, E3KARP, PDZK1, IKEPP (NHERF-1 to NHERF-4), CAL, and Shank-2 that bind to CFTR, NHE3, and the intestinal SLC26 members in the regulation of intestinal fluid transport. Current concepts are mostly derived from heterologous expression studies and studies on their role in organ physiology are still in infancy. Recently, however, PDZ adapter protein-deficient mice and organ-specific cell lines have become available, and the first results suggest a more cell-type and possibly signal-specific role of these adapter proteins. This opens the potential for drug development targeted to PDZ domain interactions, which is, in theory, one of the most efficient antidiarrheal strategies.