Surfactant replacement therapy is one of the most studied interventions in neonatal medicine, with many thousands of infants having been enrolled in randomized clinical trials. It is clear that surfactant therapy reduces neonatal mortality and the risk of pulmonary air leaks in babies with or at risk of developing respiratory distress syndrome. Yet some doubts linger over other aspects of this therapy, despite it having been an acceptable and proven therapy for the past 7-10 years. As regards timing of treatment, the earlier the better, with true prophylaxis being reserved for babies of less than 28 week's gestation. Natural surfactant preparations containing surfactant proteins B and C act more rapidly than their synthetic protein-free counterparts and probably also have a greater impact on reducing neonatal mortality and pulmonary air leaks. Fears raised about immunological effects, prion transmission and chemical contamination of natural surfactants have not been substantiated. Long-term follow-up studies do not show any differences in outcome between treated and non-treated infants, except that the incidence and severity of retinopathy of prematurity might be reduced by treatment with natural surfactant. Further research is needed and this will include more detailed follow-up studies, newer indications for surfactant therapy and the testing of newer preparations with synthetic peptides or protein analogues added.