Therapeutic use of the helium-oxygen mixture (heliox) was first reported in 1934. Medical use was further restricted to physiological studies. Density and viscosity of Heliox are very different from those of air or oxygen. This can explain how Heliox can induce modifications in the airway flow. In diseases of the main or small airways (upper airway obstruction, chronic obstructive pulmonary disease, asthma), such modifications could induce a diminution in the resistive component of the work of breathing and therefore protect against the risk of developing a respiratory failure. This explains a renewed interest of clinicians for Heliox since the beginning of the eighties. To date, the good tolerance of heliox seems to be well established. Inversely, scientific validation of the therapeutic indications of the mixture in airway diseases are lacking. Moreover, potential therapeutic indications of the mixture are not restricted to airway diseases. Various applications, such as adult respiratory distress syndrome, pneumothorax, fiberoptic bronchoscopy, and mechanical ventilation, are suggested by preliminary reports. Obtaining a synthetic vision of older and more recent studies is the purpose of this review.