CLC proteins form an evolutionary conserved gene-family that comprises nine members in mammals, at least four of which are involved in human genetic diseases. The X-ray structure of the bacterial CLC homologue, ClC-ec1, confirmed a homodimeric double-barreled architecture with two separate Cl- ion transport pathways. Four of the mammalian CLC proteins, ClC-1, ClC-2, ClC-Ka, and ClC-Kb, are Cl- ion channels that fulfill their functional roles in the plasma membrane. The other five CLC proteins are expressed in intracellular organelles. ClC-4, ClC-5, and probably also ClC-3, are not Cl- ion channels but exhibit significant Cl-/H+ antiporter activity (1, 2), similar to the bacterial ClC-ec1 (3), and with identical 2 Cl- : 1 H+ transport stoichiometry (4). Cl- and H+ transport activity of the exchanger members of the family strictly depend on two glutamate residues. Mutating a ‘gating glutamate’ (E211 in ClC-5) converts the exchanger into anion conductances. Neutralizing the ‘proton glutamate’ of (E268), but not its replacement by some other titratable groups, rather abolishes Cl- and H+ transport (5). Noise analysis indicated that ClC-5 switches between silent and transporting states with an apparent unitary conductance of 0.5 pS, indicating a very large transport turnover (5). Nitrate uncoupled the proton transport but mutating the highly conserved serine 168 to proline, as found in the plant NO3- / H+ antiporter atClCa, led to coupled NO3- : H+ exchange (4,5). We further found that ClC-5 is strongly stimulated by intracellular protons in an allosteric manner with an apparent pK of ~ 7.2 (4). Gating of the Torpedo Cl- channel ClC-0 is modulated by intracellular and extracellular pH, but the mechanism responsible for this regulation has remained so far elusive. Using inside-out patch clamp measurements we studied the dependence of the fast gate on pHint and [Cl-]int. Only the closing rate, but not the opening rate showed a strong dependence on these intracellular factors. Using mutagenesis we excluded several candidate residues as mediators of the pHint dependence. We propose a model in which a proton generated by the dissociation of an intrapore water molecule protonates E166 leading to channel opening. Deuterium isotope effects confirm that proton transfer is rate limiting for gate opening and that channel closure depends mostly on [OH-] (6). The model is in natural agreement with the finding that only the closing rate constant, but not the opening rate constant, depends on pHint and [Cl-]int. CLC proteins are a fascinating example of how a very similar protein architecture can be used to provide either a passive electrodiffusive permeation pathway or a strictly coupled secondary active ion transporter.