ABSTRACT Electroneutral cation–chloride cotransporters are widely expressed and perform a variety of physiological roles. A novel gene family of five members, encompassing a Na+–Cl− transporter, two Na+–K+–2Cl− transporters and two K+–Cl− cotransporters, encodes these membrane proteins; homologous genes have also been identified in a prokaryote and a number of lower eukaryotes. The cotransporter proteins share a common predicted membrane topology, with twelve putative transmembrane segments flanked by long hydrophilic N- and C-terminal cytoplasmic domains. The molecular identification of these transporters has had a significant impact on the study of their function, regulation and pathophysiology.