The bumetanide-sensitive Na+/K+/2Cl- cotransporter and the thiazide-sensitive Na+/Cl- cotransporter are present in a wide variety of tissues, and appear to serve physiological cell functions such as volume control, particularly the phenomenon known as regulatory volume control, and net secretion or absorption of salt. The recent cDNA cloning of these two cotransporters suggests that they are members of the same new family, because they exhibit a topology featuring 12 potential membrane-spanning helices flanked by large hydrophilic domains at the NH2- and COOH-termini. The transporters are regulated by phosphorylation directly via protein kinase and dephosphorylation via phosphatase, and perhaps secondary to decrease of Cl concentration in the cell by activated Cl channel.