Pseudomonas aeruginosa is an opportunistic pathogen that significantly contributes to morbidity and mortality in patients with cystic fibrosis. Defective mucociliary clearance associated with the absence of the functional cystic fibrosis transmembrane conductance regulator in airway epithelium plays a critical role in the initial colonization of this pathogen. P. aeruginosa, while initiating a profound inflammatory response, employs multiple mechanisms to evade immune clearance. The capacity to grow in biofilms and the selection of mutants with a mucoid phenotype are major adaptations that allow its persistence in the airways.