Work in several laboratories has led to the identification of a family of short single-span transmembrane proteins named after the invariant extracellular motif: FXYD. Four members of this group have been shown to interact with the Na,K-adenosine triphosphatase (ATPase) and alter the pump kinetics. Thus, it is assumed that FXYD proteins are tissue-specific regulatory subunits, which adjust the kinetic properties of the pump to the specific needs of the relevant tissue, cell type, or physiologic state, without affecting it elsewhere. A number of studies have provided evidence for additional and possibly unrelated functions of the FXYD proteins. This review summarizes current knowledge on the structure, function, and cellular distribution of FXYD proteins with special emphasis on their role in kidney electrolyte homeostasis.