Scaffold proteins are defined by the presence of specific protein-binding domains (e.g. PDZ domains) that assemble several proteins into functional complexes. Thus, scaffolds are critical for spatio-temporal organization and for proper regulation of intracellular signalling upon specific stimulus. Identified 15years ago, NHERF scaffold proteins contain several PDZ modules and were initially viewed as “passive linkers” between transmembrane proteins and the cortical cytoskeleton underlying the plasma membrane. New NHERF-binding molecules involved in cell signalling have been recently identified. Thus, NHERFs are now viewed as “active” key players in regulating cellular functions. EBP50 and PDZK1, two members of the NHERF family, are highly expressed in the liver where they link receptors, channels, transporters and cytosolic components. This review aims to give an overview of the emerging functions of NHERF proteins in liver physiology.