The story of cystic fibrosis (CF) research over the last decade has provided important lessons about the power and limitations of positional cloning of disease genes, the understanding of pathogenesis, and the development of new therapies. Studies in the 1980s identified defects in the chloride conductance properties of epithelial cells from CF patients (1). A turning point occurred in 1989 with the triumphant discovery of the gene responsible for CF by Collins, Riordan, Tsui and colleagues (2, 3). Analysis of the predicted translational product of the gene revealed a transmembrane protein that did not resemble a classic channel. The protein was called the CF transmembrane conductance regulator (CFTR) because of the previously described link between abnormalities in NaCl transport and the genetic defect. Isolation of the gene stimulated a bewildering array of studies aimed at defining the genetic basis of the disease and the biochemical and biophysical properties of the protein. Gene therapy experiments were initiated in patients by three independent groups within four years of the gene isolation (4). Despite tremendous progress by the field in these areas, an important consideration remains: What is the relationship between the genetic defect and the clinical manifestations of the disease that leads to chronic respiratory infection and respiratory compromise? Quinton (1) was the first to suggest that the genetic defect in CF causes abnormalities in the fluid lining the airway surface. An important function of this mucosal interface is to keep bacteria that are routinely inhaled from causing infection. The chronic respiratory infection associated with CF suggests this host defense is compromised. Critical validation of this hypothesis was provided by Smith et al.(5), who demonstrated that fluid recovered from cultured epithelial cells from normal individuals kills bacteria, while fluid from similar cultures of CF cells does not, providing the first direct link between a defect in CFTR and a breach in pulmonary host defense. This Perspective describes the emerging field of pulmonary host defense in the context of CF pathogenesis.