Evidence-based respiratory therapy for exacerbations of chronic obstructive pulmonary disease (COPD) includes oxygen, inhaled bronchodilators, and noninvasive positive-pressure ventilation. Examining the physics of gas flow, a case can be made either for or against the use of helium-oxygen mixture (heliox) in the care of patients with COPD. The evidence for the use of heliox in patients with COPD exacerbation is not strong at present. Most of the peer-reviewed literature consists of case reports, case series, and physiologic studies in small samples of carefully selected patients. Some patients with COPD exacerbation have a favorable physiologic response to heliox therapy, but predicting who will be a responder is difficult. Moreover, the use of heliox is hampered by the lack of widespread availability of an approved heliox delivery system. Appropriately designed randomized controlled trials with patient-important outcomes, such as avoidance of intubation, decreased intensive-care-unit and hospital days, and decreased cost of therapy, are sorely needed to establish the role of heliox in patients with COPD exacerbation, including those receiving noninvasive positive-pressure ventilation. Lacking such evidence, the use of heliox in patients with COPD exacerbation cannot be considered standard therapy.