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To provide a comprehensive, evidence-based review of helium–oxygen gas mixtures (heliox) in the management of pediatric respiratory diseases.A thorough, computerized bibliographic search of the preclinical and clinical literature regarding the properties of helium and its application in pediatric respiratory disease states.After an overview of the potential benefits and technical aspects of helium–oxygen gas mixtures, the role of heliox is addressed for asthma, aerosolized medication delivery, upper airway obstruction, postextubation stridor, croup, bronchiolitis, and high-frequency ventilation. The available data are objectively classified based on the value of the therapy or intervention as determined by the study design from which the data are obtained.Heliox administration is most effective during conditions involving density-dependent increases in airway resistance, especially when used early in an acute disease process. Any beneficial effect of heliox should become evident in a relatively short period of time. The medical literature supports the use of heliox to relieve respiratory distress, decrease the work of breathing, and improve gas exchange. No adverse effects of heliox have been reported. However, heliox must be administered with vigilance and continuous monitoring to avoid technical complications.