The ClC chloride channels and transporters constitute a large family of membrane proteins that is involved in a variety of physiological processes. All members share a conserved molecular architecture that consists of a complex transmembrane transport domain followed by a cytoplasmic domain. Despite the strong conservation, the family shows an unusually broad variety of functional behaviors as some members work as gated chloride channels and others as secondary active chloride transporters. The conservation in the structure and the functional resemblance of gating and coupled transport suggests a strong mechanistic relationship between these seemingly contradictory transport modes. The cytoplasmic domains constitute putative regulatory components that are ubiquitous in eukaryotic ClC family members and that in certain cases interact with nucleotides thus linking ion transport to nucleotide sensing by yet unknown mechanisms.