In mammals, nine genes code for Cl transporting CLC proteins. Several CLCs are involved in human genetic diseases. Triggered by the finding of Accardi & Miller (2004) that the bacterial CLC-ec1 is a secondary active, highly electrogenic, Cl-proton exchanger, we investigated if CLC-5, that is mutated in Dent’s disease, could similarly be a Cl-proton exchanger. We found that indeed the strongly outwardly rectifying current carried by CLC-5 is associated with a significant movement of protons. Detailed measurements, employing pH-sensitive microelectrodes, allowed us to conclude that CLC-5 and CLC-4 function as Cl-proton antiporters, while other CLCs (CLC-0, CLC-2, CLC-Ka) do not transport protons to a significant amount and are thus passive ion channels. While this finding is important to understand the physiological role of CLC-5 in endocytosis, the precise physiological function of CLC-5, and a possible direct role in vesicular acidification, remain speculative. Analysis of the CLC-0 mutation E166D, in which the ‘gating glutamate’ is substituted by Asp shed further light on the relationship between the channel and the transporter character of CLC proteins, pointing to an important role of protonation of this acidic residue from the intracellular solution as a major source of voltage dependence of channel function. In parallel studies we investigated pharmacological properties of renal CLC-K/barttin channels. Previously, we had identified a blocking site on CLC-Ka that is located in the extracellular pore mouth. Two amino acids (N/D-68 and G/E-72 in CLC-Ka and CLC-Kb, respectively) are critical to confer strong block by DIDS and 3-phenyl-CPP of CLC-Ka and weak block of CLC-Kb. Surprisingly, we now found that niflumic acid (NFA) increases CLC-Ka/Kb currents in the 10-1000 µM range. Flufenamic acid derivatives or high concentrations of NFA inhibited CLC-Ka, but not CLC-Kb, or blocker-insensitive CLC-Ka mutants, indicating that the activating binding site is distinct from the blocker binding site. These molecules provide a starting point for identification of diuretics or drugs useful in the treatment of Bartter’s syndrome.