Surfactant therapy in preterm and term born infants has been a huge success story. In the meantime, we have very detailed answers to the five essential questions of each medical therapy: which infant should be treated, when, with which drug, in/at what dose, and via which route of administration. The answers to these questions depend on the gestational age of the infant. We have focused on preterm infants <28 weeks of gestation as they are the most vulnerable and may have the maximum benefit of appropriate treatment. Therefore, we performed a sub-group analysis for data available from the published trials in infants less than 28 weeks who received less/minimal invasive surfactant administration/therapy [LISA/MIST] versus intubation-surfactant-extubation (INSURE). The need for mechanical ventilation (MV) was significantly reduced by 28 % (RR:0.72, 95%CI:0.64–0.80, n = 548 infants) after LISA/MIST. The incidence of bronchopulmonary dysplasia (BPD) was significantly decreased by 30 % (RR:0.70, 95%CI:0.66–0.75, n = 6528 infants) after LISA/MIST. No difference in mortality was noted between the two groups. In the current review, we discuss the applicability of guidelines to individual patient groups like the infants <28 weeks and emphasize the individual assessment of published data by the treating physician.