Clinical trials have evaluated the overall efficacy of surfactant therapy, as well as the relative efficacy of different surfactant preparations, the optimal timing of administration and the optimal dosage. Surfactant therapy leads to significant clinical improvement in infants at risk for, or having, respiratory distress syndrome (RDS). Clinical trials that compared the effects of synthetic or animal-derived surfactant preparations to placebo or no therapy demonstrate that surfactant therapy lead to rapid improvement in oxygenation, decreased ventilator support, decreased risk of pneumothorax, and mortality. Earlier treatment, prophylactic treatment of infants at high risk of developing RDS, and selective re-treatment leads to improved clinical outcome as well. Currently available animal-derived surfactants are superior to non-protein-containing synthetic surfactants. Ongoing evaluation will determine if important differences in animal-derived products are noted. Future trials will evaluate third-generation surfactant products and further refine what constitutes optimal use of surfactant.