Innate immunity is essential for prevention of infection in vertebrates and plants and dysfunction of single components of innate immunity may provoke severe disease. Here we describe how mutations in the cystic fibrosis transmembrane conductance regulator gene dysregulate a variety of components of the innate immune system in individuals suffering from the hereditary disease cystic fibrosis. In the airways of these individuals, functions of the mucociliary clearance system, cationic antimicrobial (poly)peptides and neutrophils and macrophages are impaired and inflammatory signal transduction pathways exaggerated. Consequently, chronic airway colonization with opportunistic bacterial pathogens develops and leads to life-threatening lung disease.