Surfactant replacement therapy (SRT) has long become the standard of care in the treatment of neonatal respiratory distress syndrome (RDS), significantly decreasing acute pulmonary morbidity and mortality in preterm infants. For decades, this beneficial replacement therapy has been administered via endotracheal tube. Despite significantly improving the outcome of RDS, however, the burden of bronchopulmonary dysplasia remains, in particular, in very immature preterm infants. Acknowledging the direct relationship between exposure to and duration of invasive mechanical ventilation and chronic lung disease, the latter has been gradually replaced by noninvasive ventilation strategies in neonatal RDS. This replacement is strongly related to the demand for similarly noninvasive modes of surfactant administration. Alternative techniques in spontaneously breathing infants have evolved, including less invasive techniques using thin catheters (less invasive surfactant administration and minimally invasive surfactant treatment) as well as nebulization of surfactant, although the latter is not ready for clinical application yet. In addition, given their therapeutic delivery to the lungs and subsequent alveolar distribution, surfactant preparations represent an attractive vehicle for pulmonary deposition of drugs in preterm infants. Further improvement of SRT and expansion of the field of application of lung surfactant may hold additional benefits, especially in the treatment of the most immature preterm infants.