Abstract  Airway epithelia absorb Na+ through the Epithelial Na+ Channel (ENaC) and secrete Cl− through the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. This balance maintains sufficient airway surface liquid (ASL) hydration to permits efficient mucus clearance, which is needed to maintain sterility of the lung. Cystic fibrosis (CF) is a common autosomal recessive inherited disease caused by mutations in the CFTR gene that lead to the reduction or elimination of the CFTR protein. CF is a multi‐organ disease that affects epithelia lining the intestines, lungs, pancreas, sweat ducts, and vas deferens, among others. CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia, and chronic infections. ENaC is negatively regulated by CFTR and in patients with CF, CFTR's absence results in a double hit of reduced Cl−/HCO3− and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption. Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus. Rehydrating CF mucus has become a recent clinical focus and yields important end points for clinical trials. However, while ENaC hyperactivity in CF airways has been detected in vivo and in vitro, recent data have brought the role of ENaC in CF lung disease pathogenesis into question. This review will focus on our current understanding of the contribution of ENaC to CF pathogenesis. This article is protected by copyright. All rights reserved