The classic entity of neonatal distress syndrome, as a lung disease expressing predominant surfactant deficiency, is currently changing to a more complex disease of the developing lung as a result of the number of extremely immature preterm infants. Prenatal factors, such as the fetal inflammatory response syndrome influence short- and long-term outcome in these premature infants presenting with respiratory distress syndrome at birth. Therefore, various previously dismissed treatment strategies, such as surfactant prophylaxis or newer anti-inflammatory approaches have to be reinvestigated in this emerging population. Despite the resurrection of a new picture of bronchopulmonary dysplasia, lung injury induced by mechanical ventilation remains a major issue in neonatal intensive care. With the advance in understanding of mechanical ventilation, it is becoming evident, that improvement in outcome can not be achieved by restoring normal lung physiology in the diseased lung using sophisticated ventilators and ventilation modes. A more disease specific ventilator strategy that will target as early as possible homogenous lung opening while at the same time avoiding overdistention of the lung, has the potential to affect outcome. The possible antiinflammatory properties of surfactant-proteins, nitric oxide and corticosteroids, despite some drawbacks, may show to have a synergistic effect. However, this needs further exploration.