The CLC gene family encodes Cl(-) channels or Cl(-)/H(+) exchangers. While our understanding of their structure-function relationship has greatly benefited from the crystal structure of bacterial homologues, human inherited diseases and knock-out mice were crucial in deciphering their physiological roles. Several vesicular CLC Cl(-)/H(+) exchangers are expressed in the proximal tubule (PT). ClC-5 mutations cause Dent's disease which is associated with low molecular weight proteinuria and kidney stones. ClC-5 knock-out mice revealed impaired endocytosis as the primary defect in Dent's disease. It extends to receptor-mediated and fluid-phase endocytosis and entails changes in calciotropic hormones that result in kidney stones. No renal functions could be assigned so far to ClC-3 and ClC-4, which are also expressed in PTs. Loss of ClC-7 or its beta-subunit Ostm1 entails lysosomal storage in the PT, in addition to the neuronal lysosomal storage and osteopetrosis that are the hallmarks of ClC-7/Ostm1 loss in mice and men.