The airways of patients afflicted with cystic fibrosis (CF) are colonized by many pathogens, the most predominant of which is the Gram-negative bacterium Pseudomonas aeruginosa. In the thick CF airway mucus, P. aeruginosa forms antibiotic- and phagocyte-resistant structures known as biofilms, which enable the survival and growth of the organism. P. aeruginosa can undergo dramatic genetic, physiological and morphological changes in this milieu. Chronic infection leads to a considerably reduced oxygen tension, and it is believed that some bacteria grow anaerobically, especially during late-stage disease. In this article, factors that enable long-term survival of P. aeruginosa and two novel drug targets (the rhl quorum-sensing circuit and the anti-sigma factor, MucA) are discussed. Mutants lacking these factors might be uniquely susceptible to nitrogen oxide, specifically the nitrite anion (NO(2)(-)), in the treatment of P. aeruginosa airway infections in CF.