Denufosol is a novel second-generation, metabolically stable, selective P2Y(2) receptor agonist. As ion channel regulator denufosol corrects the ion transport defect and increases the overall mucociliary clearance in cystic fibrosis (CF) lung disease by increasing chloride secretion, inhibiting sodium absorption, and increasing ciliary beat frequency in the airway epithelium independently of cystic fibrosis transmembrane conductance regulator genotype. Denufosol improved lung function relative to placebo in cystic fibrosis patients with normal to mildly impaired lung function. The drug half-life is 25 hours in ex vivo CF sputum and 3 hours when added in vitro to human respiratory epithelial cultures. Denufosol has been generally well-tolerated in healthy volunteers and patients with cystic fibrosis. The most common adverse events were in the respiratory system, with cough having the highest frequency.