The importance of pulmonary surfactant in maintaining normal lung function, and the observations that alterations in endogenous surfactant contribute to the lung dysfunction associated with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), provide a rationale for administering exogenous surfactant in this setting. The results of clinical trials have been variable, however, in part due to the various surfactant preparations used, the different delivery and dosing methods employed, and the types of patients targeted for this therapy. Based on the insight gained from these studies, ongoing trials have modified these factors to optimize outcome, including one trial that is focusing on patients with direct lung insults such as pneumonia and aspiration.