The pharmacology, clinical efficacy, and cost considerations of exogenous lung surfactants are reviewed.Exogenous pulmonary surfactants, along with advancements in ventilatory care, have significantly reduced the incidence of respiratory distress syndrome (RDS) and its related complications in infants. The following exogenous surfactants are approved for the prophylaxis and treatment (rescue) of neonatal RDS: beractant, a modified natural surfactant; calfactant and poractant, both natural surfactants; and colfosceril, a synthetic surfactant that is not currently available in the United States. Lucinactant, a synthetic surfactant, is under investigation and received approvable status from the Food and Drug Administration in February 2005. The surfactants are delivered directly to their site of action, and only small amounts reach the systemic circulation. Bioavailability to the distal airways and alveoli depends on the method of delivery, the stage and severity of pulmonary disease, and the properties of the particular surfactant. According to data from clinical trials, the use of exogenous surfactant therapy for rescue within the first two hours of life appears to be as efficacious as prophylaxis in most premature infants.Comparative trials of surfactants have proven the efficacy of both synthetic and natural surfactants in the prevention and treatment of RDS. However, these trials have universally demonstrated greater reduction in the immediate need for ventilator support in infants who receive natural surfactants. Natural preparations cause less pneumothorax, bronchopulmonary dysplasia, and mortality compared with synthetic preparations. Synthetic agents offer the potential advantages of an unlimited supply with consistent pharmaceutical quality and no risk of transmitting infectious disease or causing immunologic sensitization.