Increased airway Na⁺ absorption mediated by the amiloride-sensitive epithelial Na⁺ channel (ENaC) is a basic defect in cystic fibrosis (CF) lung disease. CF belongs to the most common lethal hereditary diseases and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)gene. CFTR acts as a cAMP-dependent Cl^- channel and regulator of ENaC, and CFTR dysfunction causes impaired Cl^- secretion and increased Na⁺ absorption in CF airways. Evidence from in vitro studies suggested that increased Na⁺ absorption produces airway surface liquid (ASL) volume depletion and led to the generation of transgenic mice with airway specific overexpression of ENaC to elucidate the role of this mechanism in the in vivo pathogenesis of lung disease. Studies of the pulmonary phenotype of bENaC-overexpressing mice demonstrated that increased airway Na⁺ absorption caused ASL depletion and reduced mucus transport producing a CF-like lung disease with airway mucus plugging, chronic airway inflammation and pulmonary mortality. Further, recent pharmacological studies demonstrated that preventive, but not late, inhibition of increased airway Na⁺ absorption with the ENaC blocker amiloride reduced morbidity and mortality in this murine model of CF lung disease. These results support a critical role of ENaC in the in vivo pathogenesis of CF lung disease and suggest that amiloride may be an effective preventive therapy for CF patients.