Non-invasive ventilation (NIV) commenced soon after birth is highly effective in providing mechanical respiratory support for preterm infants with respiratory distress syndrome (RDS). However, NIV alone frequently fails to provide adequate respiratory support for infants with more significant respiratory compromise due to RDS. Without an endotracheal tube as the conduit to administer exogenous surfactant in such cases, less invasive approaches to surfactant delivery have emerged, with those involving the use of a thin catheter (termed minimally invasive surfactant therapy, MIST) now in the ascendancy. The application of MIST with NIV support continuing allows spontaneous breathing to be harnessed for optimal surfactant dispersal to the distal airspaces. Here we examine the importance of this pairing of NIV with MIST and review the evidence for optimization of NIV before, during and after delivery of surfactant. All evidence points to NIV and MIST being an elegant and synergistic pairing of two therapies for optimal respiratory support of preterm infants in early life. Whilst much of the clinical trial data regarding the pairing of NIV and MIST relates to application of standard continuous positive airway pressure, non-invasive positive pressure ventilation in its various forms may offer additional advantage, and further studies are warranted.