Surfactant replacement therapy, a major breakthrough in the care of neonates born preterm, remains an exciting and extensively researched field. From the initial days of routine intubation and prophylactic surfactant administration coupled with ongoing invasive mechanical ventilation, to the predominant present-day approach of less invasive surfactant administration, practices have evolved considerably. However, the question neonatologists often ponder is at what threshold clinicians should decide on surfactant therapy use in a neonate born preterm who has respiratory distress syndrome (RDS) and is being treated with noninvasive respiratory support, such as continuous positive airway pressure (CPAP), in which the threshold is commonly defined by the fraction of inspired oxygen (FiO2), level of CPAP usage, and to a lesser extent, clinical factors, such as work of breathing.