Cystic fibrosis is caused by a defective expression of the cystic fibrosis transmembrane conductance regulator (Cftr) gene, which results in chronic pulmonary inflammation and infections. The pathophysiological mechanisms by which these changes are induced in the lungs of patients with cystic fibrosis require definition. This study found that Cftr deficiency in mice results in the upregulation and activation of CD95. CD95 activation is caused by increased ceramide concentrations in cystic fibrosis lungs, as revealed by genetic modifications that normalize pulmonary ceramide concentrations. The activation of CD95 in cystic fibrosis lungs further increases pulmonary ceramide levels and results in a vicious feedback cycle of CD95 activation and ceramide accumulation. Genetic studies reveal that CD95 is crucially involved in the induction of aseptic inflammation, an increase in the bronchial cell death rate, and an increased susceptibility to infection of Cftr-deficient mice. All of these pathologies are partially corrected by heterozygosity of CD95 in Cftr-deficient mice. These findings identify CD95 as an important regulator of lung functions in cystic fibrosis and suggest that CD95 may be a novel target for treating cystic fibrosis.