The four members of the NHERF family of PDZ-adapter proteins bind to a variety of membrane transporters and receptors, and modulate membrane expression, mobility, interaction with other proteins, and the formation of signalling complexes. All four family members are expressed in the intestine. The CFTR anion channel and the Na⁺/H⁺ exchanger NHE3 are two prominent bindings partners to this PDZ-adapter family, which are also known to be key players in the regulation of intestinal electrolyte and fluid transport. Experiments in heterologous expression systems have provided a number of mechanistic models how NHERF proteins can interact with some of their targets on a molecular level. Recently, however, NHERF1,2 and 3 knockout mice have become available, and this presentation will highlight the findings on electrolyte and fluid transport regulation in the native intestine of these mice.