CLC chloride channels and transporters were originally identified by the cloning of ClC-0 from the electric organ of Torpedo marmorata. They constitute a gene family with members in all phylae. The crystal structure of bacterial CLC proteins, which function as Cl-/H+ exchangers, now allows detailed structure-function studies. There are nine different CLC genes in mammals that can be grouped into three homology groups. Members of the first group function as plasma membrane chloride channels. Depending on the gene, their mutational inactivation in human genetic diseases or mouse models leads to diseases to myotonia, infertility, blindness, renal salt and deafness. Members of the two other branches are mainly located on endosomes and lysosomes. ClC-4 and ClC-5 were shown to function as Cl-/H+ exchangers, which may apply for the other intracellular CLCs as well. They are thought to facilitate the acidification of these compartments by neutralizing currents of the H+-ATPase. In humans, mutations in ClC-5 cause the kidney stone disorder Dent's disease, and ClC-7 osteopetrosis and lysosomal storage disease.

Two beta-subunits for CLC proteins are known: barttin is a beta-subunit for ClC-K Cl channels, and Ostm1 a beta subunit for ClC-7. Both are essential for function and their mutational inactivation leads to human disease.