Toward the end of gestation in mammals, the fetal lung undergoes a process of differentiation that is required for transition to air breathing at birth. Respiratory epithelial cells synthesize the surfactant proteins and lipids that together form the pulmonary surfactant complex necessary for lung function. Failure of this process causes respiratory distress syndrome, a leading cause of perinatal death and morbidity in newborn infants. Here we demonstrate that expression of the forkhead gene Foxa2 in respiratory epithelial cells of the peripheral lung controls pulmonary maturation at birth. Newborn mice lacking Foxa2 expression in the lung develop severe pulmonary disease on the first day of life, with all of the morphological, molecular, and biochemical features of respiratory distress syndrome in preterm infants, including atelectasis, hyaline membranes, and the lack of pulmonary surfactant lipids and proteins. RNA microarray analysis at embryonic day 18.5 demonstrated that Foxa2-regulated expression of a group of genes mediating surfactant protein and lipid synthesis, host defense, and antioxidant production. Foxa2 regulates a complex pulmonary program of epithelial cell maturation required for transition to air breathing at birth.