Cl- channels are involved in a range of functions, including regulation of cell volume and/or intracellular pH, acidification of intracellular vesicles, and vectorial transport of NaCl across many epithelia. Numerous Cl- channels have been identified in the kidney, based on single-channel properties such as conductance, anion selectivity, gating, and response to inhibitors. The molecular counterpart of many of these Cl- channels is still not known. This review will focus on gene-targeted mouse models disrupting two structural classes of Cl- channels that are relevant for the kidney: the CLC family of voltage-gated Cl- channels and the CFTR. Disruption of several members of the CLC family in the mouse provided useful models for various inherited diseases of the kidney, including Dent's disease and diabetes insipidus. Mice with disrupted CFTR are valuable models for cystic fibrosis (CF), the most common autosomal recessive, lethal disease in Caucasians. Although CFTR is expressed in various nephron segments, there is no overt renal phenotype in CF. Analysis of CF mice has been useful to identify the role and potential interactions of CFTR in the kidney. Furthermore, observations made in CF mice are potentially relevant to all other models of Cl- channel knockouts because they emphasize the importance of alternative Cl- pathways in such models.