 Previous work demonstrated that inhaled hypertonic saline HS reduces exacerbation frequency and improves lung function in patients with clinically apparent lung disease. A number of issues revolving around the use of HS in CF remain unresolved. First, the typical patients enrolled in previous studies were adults mean age 26 yrs with established lung disease mean FEV178. Despite our hypothesis that HS should positively affect MCC in preservednormal airways, a common view of HS is that it benefits CF patients by inducing cough and transiently promoting the clearance of thick CF secretions. It has been questioned, therefore, whether HS will benefit patients who are younger and have mild or undetectable lung disease and potentially normal though unmeasured rates of MCC. Second, it is unclear whether the substantial beneficial effects of HS in CF were achieved because of a long 4 hours duration of action or in spite of an extremely short 45 minutes duration of action the traditional view based upon experiments in normal epithelia. This issue is important, as it relates to the development and dosing of hydrator therapies that may have different pharmacodynamic profiles. Certainly, if twice daily dosing of a short acting compound is sufficient to provide significant clinical benefit, it would reduce the challenge of drug discovery for CF and ease the treatment burden imposed upon patients. The study of HS in CF provides us an opportunity to address this issue. 