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ABSTRACT Intro: Extracorporeal membrane oxygenation for neonatal and pediatric respiratory failure continues to demonstrate improving outcomes, largely due to advances in technology along with refined management strategies despite mounting patient acuity and complexity. Successful use of ECMO requires thoughtful initiation and candidacy strategies, along with reducing the risk of ventilator induced lung injury and the progression to multiorgan failure. Areas Covered: This review describes current ECMO management strategies for neonatal and pediatric patients with acute refractory respiratory failure and summarizes relevant published literature. ECMO initiation and candidacy, along with ventilator and sedation management, are highlighted. Additionally, rapidly expanding areas of interest such as anticoagulation strategies, transfusion thresholds, rehabilitation on ECMO, and drug pharmacokinetics are described. Expert Opinion: Over the last few decades, published studies supporting ECMO use for acute refractory respiratory failure, along with institutional experience, have resulted in increased utilization although more randomized-controlled trials are needed. Future research should focus on filling the knowledge gaps that remain regarding anticoagulation, transfusion thresholds, ventilator strategies, sedation, and approaches to rehabilitation to subsequently implement into clinical practice. Additionally, efforts should focus on well-designed trials, including population pharmacokinetic studies, to develop dosing recommendations.