Long-term oxygen therapy in patients with pronounced hypoxia is an important and life-extending therapy. Many patients have only mild hypoxia, do not experience nocturnal desaturation, or experience desaturation only during exercise. While often applied in clinical practice, the clinical relevance of oxygen therapy was not clear in these patients. A recent randomized controlled trial has now revealed no additional value for long-term oxygen therapy in subjects with mild oxygen desaturation or exercise-induced oxygen desaturation only. Furthermore, treatment burden, adverse events and healthcare costs associated with oxygen therapy need to be considered; restriction of the prescription of oxygen therapy is, therefore, appropriate. On the other hand, oxygen therapy is still considered important in non-severe hypoxic subjects with severe exercise-related desaturation (< 80%); in selected cases during endurance training in pulmonary rehabilitation; or in individual subjects with desaturation and pronounced and proven benefit of oxygen therapy on their symptoms and exercise capacity.