Human airways normally regulate the volume of a thin liquid layer, the periciliary liquid (PCL), to provide the mucus clearance component of lung defense (REF 1). Studies under standard (static) culture conditions revealed that normal airway epithelia possess an adenosine (ADO)-regulated pathway that blends Na⁺ absorption and Cl^– secretion to optimize PCL volume. In CF, the absence of CFTR results in a failure of ADO regulation of PCL volume, which is predicted to initiate mucus stasis and infection. However, under conditions that mimic the phasic motion of the lung in vivo, ATP release into PCL was increased, CF ion transport rebalanced, and PCL volume restored to levels adequate for lung defense. This ATP signaling system was vulnerable, however, to insults that trigger CF bacterial infections, such as viral (RSV) infections, which upregulated extracellular ATPase activity and abolished motion-dependent ATP regulation of CF PCL height. These studies demonstrate (i) how the normal coordination of opposing ion transport pathways to maintain PCL volume is disrupted in CF; (ii) the hitherto unknown role of phasic motion in regulating key aspects of normal and CF innate airways defense; and (iii) that maneuvers directed at increasing motion-induced nucleotide release may be therapeutic in CF patients.