In addition to the established treatment of neonatal respiratory distress syndrome by oxygen supplementation, artificial ventilation and thermoneutrality, substitution of surfactant offers a new therapeutic perspective. Up to now, either artificial mixtures of surface active components or surfactant extracts from minced animal lungs, lung lavage fluid, or human amniotic fluid have been used in controlled trials of prophylactic and rescue surfactant treatment. Meta-analysis of controlled prevention trials including about 2,400 preterm infants shows decreased mortality (21% in controls, 9.5% in infants treated with natural preparations, p less than 0.001; 17% in controls, 11% in infants treated with artificial preparations, p less than 0.001) and fewer complications of artificial ventilation (pneumothorax: 24 vs. 7.2% with natural preparations, p less than 0.001; 20 vs. 15% with artificial preparations, p less than 0.05). In rescue studies on more than 1,900 preterm infants, natural surfactant preparations decreased complications of artificial ventilation such as pulmonary interstitial emphysema and pneumothorax (32 vs. 13%, p less than 0.001). Although the immediate effect of artificial preparations is mild, the incidence of pneumothorax also could be reduced (30 vs. 19%, p less than 0.001). Mortality could be reduced by 1/3 with natural (31 vs. 20%, p less than 0.001) and with artificial preparations (23 vs. 16%, p less than 0.01). The incidence of bronchopulmonary dysplasia and intracerebral hemorrhage, however, did not drop significantly. Severe adverse side effects of this treatment seem to be rare. There are, however, potential hazards of surfactant substitution. Its use should be restricted to fully staffed and equipped neonatal intensive care units.