It is increasingly being recognized that cells coordinate the activity of separate ion channels that allow electrolytes into the cell. However, a perplexing problem in channel regulation has arisen in the fatal genetic disease cystic fibrosis, which results from the loss of a specific Cl^- channel (the CFTR channel) in epithelial cell membranes. Although this defect clearly inhibits the absorption of Na⁺ in sweat glands^,, it is widely accepted that Na⁺ absorption is abnormally elevated in defective airways in cystic fibrosis^,. The only frequently cited explanation for this hypertransport is that the activity of an epithelial Na⁺ channel (ENaC) is inversely related to the activity of the CFTR Cl^- channel^,,. However, we report here that, in freshly isolated normal sweat ducts, ENaC activity is dependent on, and increases with, CFTR activity. Surprisingly, we also find that the primary defect in Cl^- permeability in cystic fibrosis is accompanied secondarily by a Na⁺ conductance in this tissue that cannot be activated. Thus, reduced salt absorption in cystic fibrosis is due not only to poor Cl^- conductance but also to poor Na⁺ conductance.