Although known for more than 20 years, the molecular identity of epithelial Ca²⁺-activated Cl⁻ channels remains obscure. Previous candidate proteins did not hold initial promises, and thus, new hope is put into the recently identified family of bestrophin proteins, as they reflect many of the properties found for native channels. Mutations in the bestrophin gene cause an autosomal form of macular dystrophy of the retina. Bestrophin 1 is assumed to form the basolateral Ca²⁺-activated Cl⁻ channel in the retinal pigment epithelium of the eye. Other data suggest that bestrophin is a regulator of voltage gated Ca²⁺ channels. Structural information on bestrophins is available and a Cl⁻ selective filter has been localized to the second transmembrane domain of bestrophin. It is possible that bestrophins function as physiologically regulated Cl⁻ channels only in association with additional subunits and auxiliary proteins. Little is known about expression of bestrophin in gland acinar cells, which show a pronounced Ca²⁺-activated Cl⁻ secretion. In airways and intestinal epithelia, bestrophins could be particularly important in diseases such as cystic fibrosis and secretory diarrhea.