In the past decade, there has been remarkable progress in understanding of the roles of Cl(-) channels in the development of human diseases. Genetic studies in humans have identified mutations in the genes encoding Cl(-) channels which lead to a loss of Cl(-) channel activity. These mutations are responsible for the development of a variety of deleterious diseases in muscle, kidney, bone and brain including myotonia congenita, dystrophia myotonica, cystic fibrosis, osteopetrosis and epilepsy. Recent studies indicate that some diseases may develop as a result of Cl(-) channel activation. There is growing evidence that the progression of glioma in the brain and the growth of the malaria parasite in red blood cells may be mediated through Cl(-) channel activation. These findings suggest that Cl(-) channels may be novel targets for the pharmacological treatment of a broad spectrum of diseases. This review discusses the proposed roles of abnormal Cl(-) channel activity in the pathogenesis of human diseases.