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Respiratory distress syndrome (RDS) is a major contributor to neonatal mortality worldwide. However, little information is available regarding rates of RDS-specific mortality in low-income countries, and technologies for RDS treatment are used inconsistently in different health care settings. Our objective was to better understand the interventions that have decreased the rates of RDS-specific mortality in high-income countries over the past 60 years. We then estimated the effects on RDS-specific mortality in low-resource settings. Of the sequential introduction of technologies and therapies for RDS, widespread use of oxygen and continuous positive airway pressure were associated with the time periods that demonstrated the greatest decline in RDS-specific mortality. We argue that these 2 interventions applied widely in low-resource settings, with appropriate supportive infrastructure and general newborn care, will have the greatest impact on decreasing neonatal mortality. This historical perspective can inform policy-makers for the prioritization of scarce resources to improve survival rates for newborns worldwide. Pediatrics 2011;127:1139-1146