Mucociliary clearance in the lung epithelium is a critical protective function and is essential for the clearance of respiratory pathogens. Maintenance of the periciliary layer requires the careful coordination of Na+ absorption through epithelial Na+ (ENaC) and cation channels and Cl- secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). In cystic fibrosis (CF), defective CFTR expression and activity lead to chronic bacterial respiratory infections, airway obstruction, bronchiectasis, and respiratory failure. Two recent models, the Beta ENaC overexpressing mouse and the CF pig, have shed light on the underlying mechanisms that cause dysfunction in CF. Altered fluid regulation in the airway epithelium is consistently observed in many respiratory infections. Influenza infection can lead to respiratory symptoms such as pneumonia, pulmonary edema, and acute respiratory distress syndrome in severe cases. Alteration of ENaC by influenza occurs through protein kinase C activation initiated by hemagglutinin binding during virus attachment. Influenza also decreases fluid clearance in vivo by nucleotide/nucleoside signaling well before changes in lung morphology occur. Finally, the matrix protein 2, an ion channel expressed during influenza infection, inhibits both ENaC and CFTR activity.