The epithelial sodium channel (ENaC) represents the rate-limiting step of sodium absorption across airway epithelia and thereby constitutes the major pathway for volume absorption from the airway surface liquid compartment. ENaC dysregulation leads to dehydration of airway surfaces in patients with cystic fibrosis, which in turn disrupts the primary innate lung defense mechanism, mucus clearance. The development of treatment strategies that address this defect is a logical and promising means of preventing or delaying the onset of this lethal lung disease.