The neonatal respiratory distress syndrome (RDS), caused by surfactant deficiency, is characterized by a nonuniform distribution of tidal volumes in the lung parenchyma, epithelial necrosis in peripheral airspaces, and leakage of protein into the alveoli from areas of epithelial disruption. Studies on premature experimental animals have shown that the leakage of protein is correlated to the pressure required to ventilate the lungs, i.e. presumably to the degree of surfactant deficiency. Since the leaking material includes potent surfactant inhibitors, the underlying surfactant deficiency may become aggravated, and a vicious cycle is easily established. Lung compliance is improved, epithelial necrosis prevented, and protein leakage significantly reduced by instillation of surfactant into the airways of immature newborn experimental animals. This provides the rationale for surfactant replacement therapy in neonatal RDS.