Failure to clear mucus normally is a critical event in the pathogenesis of chronic bronchitis (CB). A unifying concept for the failure to clear mucus from airway surfaces has emerged that focuses on an abnormally high mucin-to-airway surface liquid volume ratio. At a certain level, a high mucin-to-volume ratio is associated with loss of the periciliary liquid layer and adhesion of the mucus layer to the cell surface. Adherent mucus becomes a stimulus for irritation and cough and is the nidus for bacterial infection. Therapeutic approaches for clearing mucus from CB airways should focus on restoring the balance of mucin and water. Pharmacologic blockade of the epithelial Na+ channel, which is rate-limiting for volume absorption from airway surfaces, constitutes a novel therapeutic target. Studies of mucus clearance both in sheep models and human subjects demonstrate that blockade of the epithelial Na+ channel is associated with an acceleration of mucus clearance, suggesting that epithelial Na+ channel blockade may indeed constitute a rational form of therapy for CB.