Cystic fibrosis is one of the most common autosomal recessive disorders, at least in Western countries. Patients with cystic fibrosis exhibit many symptoms, the most important of which are chronic inflammation and bacterial infections of the lung. Cystic fibrosis is caused by mutations of the cystic fibrosis conductance regulator (CFTR) gene; however, the molecular mechanisms leading to the clinical manifestations of cystic fibrosis are still unclear. Here we discuss recent findings related to the role of sphingolipids, in particular ceramide, in cystic fibrosis and the bacterial infections associated with that disease. Ceramide accumulates in the lungs of cystic fibrosis mice and causes pulmonary inflammation, infection, and cell death, events that are corrected by the genetic deletion or pharmacological inhibition of acid sphingomyelinase; this inhibition normalizes ceramide concentrations in murine models of cystic fibrosis. Initial clinical studies suggest that pharmacological inhibition of acid sphingomyelinase may be a novel strategy for treating patients with cystic fibrosis.