Helium-oxygen (“heliox”) mixtures have been used for decades in the treatment of various respiratory problems ranging from acute upper airway obstructions to lower airway derangements, such as asthma and exacerbations of chronic bronchitis. This review presents a brief history of helium and helium-oxygen mixtures and their potential clinical uses, summarizes the results of past research into heliox in respiratory applications, explains the physiology of heliox, and presents more recent literature relating to heliox in the clinical setting.