Natural surfactants consist of unique proteins and lipids. Their effectiveness in improving subnormal lung function in surfactant deficiency should be established prior to any clinical trials. Rigorous tests are required to document batch to batch variability in surface activity and to exclude toxic contaminants. Up to this date randomized clinical trials in small preterm infants have demonstrated a striking improvement in lung function, and a decrease in incidence of acute complications (pneumothorax, interstitial emphysema). Administration of human surfactant at birth or in severe RDS decreased deaths and incidence of bronchopulmonary dysplasia. Although homologous surfactant may not be more advantageous than the heterologous one in terms of its acute beneficial effects on lung function, the safety and efficacy of animal surfactant in improving the outcome remains to be established. Human surfactant may serve as a model for unlimited natural surfactant produced by gene technology. The pharmacodynamics aspects of surfactant substitution, the indications of exogenous surfactant, and the management of the patients undergoing surfactant substitution remain to be studied. Exogenous surfactant offers a potential to treat or prevent severe respiratory failure in infants, children and adults.