Morbidity and mortality in cystic fibrosis (CF) patients is strongly related to their respiratory disease. We have analyzed, by means of in situ hybridization, the localization and levels of CFTR mRNA in fetal, newborn, and infant respiratory tissues. Measurable levels of CFTR transcript are present in the fetal primordial epithelium of the pseudoglandular stage lung. During the following stages of lung development, CFTR expression decreases in cells of the future alveolar spaces and is gradually limited to the epithelium of the small airways. After birth, expression decreases in the small airways and is not detected in alveolar epithelia. In trachea and large bronchi, a differential pattern of expression is also observed. No CFTR expression is found in fetal submucosal glands during fetal development, but appears gradually in the newborn period. Since CFTR codes for a secretory Cl- channel, these data probably reflect the changes that occur in the lung transition from a fluid-secreting to an absorbing organ. The pattern of expression seems paradoxical in view of the clinical-pathological manifestations of CF. Although CFTR is expressed in the normal fetus and lung development is influenced by the amount of fetal lung liquid, newborns affected with CF have normal lungs. In addition, the earliest pathologic change described in CF lungs in hyperplasia of the submucosal glands, yet expression in these structures is seen only after birth. An improved understanding of the factors that alter the expected relationship between CFTR expression and pathologic lesions in the fetal lung may provide important insights into the pathogenesis and potential treatment of lung disease in CF patients.