1. A protein isolated from the bovine tracheal epithelium behaves as a Ca2+-activated Cl- channel (CaCC) when incorporated into planar lipid bilayers. 2. An antibody raised against this protein was used to screen a cDNA expression library and resulted in the isolation of a cDNA clone that exhibited nearly identical electrophysiological characteristics to the isolated endogenous protein when expressed. 3. Recent cloning of several related proteins has revealed that the cloned bovine CaCC is one of a large and growing family. All new family members so far examined are associated with the appearance of a novel Ca2+-mediated Cl- conductance when heterologously expressed. 4. This new group of proteins may underlie the Ca2+-mediated Cl- conductance upregulated in the cystic fibrosis (CF) knockout mouse and thought to be responsible for the escape from the significant airway pathology associated with CF.