The cystic fibrosis transmembrane conductance regulator (CFTR) forms an epithelial anion channel with complex regulation. It is principally expressed in the apical membrane of epithelia, where it controls the rate of fluid flow through its roles as an ion channel and transport regulator. The importance of CFTR for transepithelial ion transport is dramatically highlighted by its malfunction in human disease. Mutations that, in general, abolish the function of CFTR cause the genetic disease cystic fibrosis (CF). By contrast, secretory diarrhoea and autosomal dominant polycystic kidney disease (ADPKD) involve unphysiologic activation of CFTR. In the search for rational new therapies for diseases associated with CFTR malfunction, small molecules that interact directly with CFTR have been identified. Some agents (e.g. phloxine B) rescue the Cl channel function of CF mutants by potentiating channel gating. These agents interact with the nucleotide-binding domains (NBDs) of CFTR to promote, and stabilise, the formation of an NBD dimer, which controls channel gating. By contrast, a variety of organic anions (e.g. glibenclamide) are open-channel blockers of the CFTR Cl channel. These agents bind within the deep wide vestibule at the intracellular end of the CFTR pore and prevent Cl flow through the channel. Knowledge of the molecular pharmacology of CFTR is leading to the development of new treatments for diseases caused by the malfunction of CFTR.