We used the isolated skin of Xenopus laevis to investigate the relationship between the secretion of salt, water, and mucus by submucosal glands expressing the cystic fibrosis transmembrane conductance regulator (CFTR). In situ hybridization and immunofluorescence provided evidence for specific expression of CFTR in the mucus-secreting cells of the subepidermal glands. Stimulation of isolated sheets of skin with 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate produced active Cl secretion and a marked increase in tissue conductance that was correlated with mucous cell degranulation and the distention of the glandular ducts. This coordinated increase in active secretion of salt and mucus was abolished by pretreatment of skins with bumetanide or by removing Cl from the bathing solutions. These results provide evidence for an intimate coupling between electrolyte transport and mucus secretion that may illuminate the pathophysiology of mucus-producing glands in cystic fibrosis lung disease.