We searched the MEDLINE, CINAHL, and Cochrane Library databases for English-language randomized controlled trials, systematic reviews, and articles investigating surfactant replacement therapy published between January 1990 and July 2012. By inspection of titles, references having no relevance to the clinical practice guideline were eliminated. The update of this clinical practice guideline is based on 253 clinical trials and systematic reviews, and 12 articles investigating surfactant replacement therapy. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation scoring system: 1: Administration of surfactant replacement therapy is strongly recommended in a clinical setting where properly trained personnel and equipment for intubation and resuscitation are readily available. 2: Prophylactic surfactant administration is recommended for neonatal respiratory distress syndrome (RDS) in which surfactant deficiency is suspected. 3: Rescue or therapeutic administration of surfactant after the initiation of mechanical ventilation in infants with clinically confirmed RDS is strongly recommended. 4: A multiple surfactant dose strategy is recommended over a single dose strategy. 5: Natural exogenous surfactant preparations are recommended over laboratory derived synthetic suspensions at this time. 6: We suggest that aerosolized delivery of surfactant not be utilized at this time.