In this paper current knowledge of the pulmonary surfactant system with particular emphasis on aspects that relate to exogenous surfactant replacement therapy for the neonatal respiratory distress syndrome (RDS) is considered. The work provides an overview, but concentrates on several facets of lung surfactant research that help to elucidate and evaluate past and present attempts toward such therapy. Subjects addressed include the functional need for specific lung surfactant components to obtain optimal surface activity and some of the required surface property measurements to characterize such activity. Also discussed is current knowledge of lung surfactant synthesis and secretion and the potential effect of exogenous surfactant on the endogenous pulmonary surfactant system. A primary theme throughout is that an analysis of previous clinical trials involving surfactant replacement shows the necessity for strong interactions with related basic science investigations. It is suggested that future human infant surfactant replacement trials proceed deliberately, and include maximal correlations with basic in vitro research on lung surfactant biophysics and biochemistry and with experiments in animal models.