Two hypotheses of how airway surface liquid (ASL) differs in healthy and CF lungs. (a) The high salt hypothesis (9, 10) postulates that normal ASL has low levels of salt as a result of salt absorption in excess of water (A1, left). Even though the epithelium is water permeable, salt is retained in thin surface films by some combination of surface tension (28) and impermeant osmolytes (10). In CF (A2), salt is poorly absorbed resulting in excessively salty ASL that disrupts natural mucosal antibiotics. Key features of the high salt model are: the lack of an appreciable shunt Cl^– conductance, central importance of CFTR's channel role, no specific role for inhibition of ENaC by CFTR, and a switch from isotonic volume absorption to hypertonic salt absorption as the surface layer thins and traps residual water. (b) The low volume hypothesis (14) postulates that normal ASL (B1) has salt levels approximately equal to plasma. In CF (B2), the removal of CFTR's inhibition of ENaC results in abnormally elevated isotonic fluid absorption which depletes the ASL and leads to reduced mucociliary clearance. Key features of the low volume model are the parallel pathway for Cl^– via shunt pathway(s) and inhibition of ENaC via CFTR.