Mucus clearance on airway surfaces is a primary form of pulmonary defense. The efficiency of mucus clearance in large part depends on the volume of the airway surface liquid components, including both the periciliary liquid (PCL) layer and the mucus layer. Studies with in vitro model systems suggest that the mucus layer acts as a passive reservoir to redistribute water to and from, as needed, the PCL layer. In contrast, the overall volume of airway surface liquid is determined by active transepithelial salt transport. Data from in vitro systems suggest that airway epithelia have the capacity to both absorb and secrete liquid in response to the volume requirements on the apical surface. At present, the nature of the signals that transmit information about airway surface liquid volume to epithelia and their sensors are unknown. However, progress in elucidation of this system is important, because it appears that these systems are deranged in the genetic disease cystic fibrosis, which is characterized by airway surface liquid volume depletion, mucus stasis, and chronic infection. Thus, insights into these systems may offer novel therapeutic opportunities to correct this physiologic dysfunction of airway epithelia.