Humidified high-flow nasal cannula (HHFNC) therapy for neonates has become increasingly popular in recent years. It is frequently used in circumstances when continuous positive airway pressure (CPAP) might otherwise have been used. Limited evidence is available to support the specific role, efficacy, and safety of HHFNC in newborns. This evidence suggests that HHFNC provides inconsistent and relatively unpredictable positive airway pressure, but may be effective in the treatment of some neonatal respiratory conditions while being more user-friendly for caregivers than conventional CPAP. Concerns regarding infection risks have resulted in one major HHFNC device being withdrawn from the market before being recently reintroduced. Caution should be exercised in the use of HHFNC in neonates (eg, by limiting its use to relatively lower flows and to relatively larger neonates, while collecting and closely monitoring safety and efficacy data) until further evidence is available to clearly delineate its role, as well as to support its safety and efficacy.