Following current guidelines, spontaneous pneumothorax should be primarily managed with minimal invasive strategies. In real-world clinical practice, oxygen supplementation regardless of the presence or absence of hypoxemia is frequently applied in patients with a pneumothorax, with the intention to enhance the resorption rate of air from the pleural cavity (“nitrogen wash-out theory”). This review provides an overview of the scientific origin of this practice in animal models, and its clinical use in adult and paediatric patients. Clinical studies from PubMed, Embase and Cochrane library were reviewed by the authors using the keywords, “oxygen AND pneumothorax”, “nitrogen washout AND pneumothorax” and “nitrogen AND pneumothorax”, and recommendations from current guidelines were also reviewed by the authors. A selected total of nine clinical studies and three guidelines were included. Though in animal models there appears to be a therapeutic effect of oxygen therapy for the treatment of pneumothorax, clinical data in patient populations mainly stem from retrospective studies, mostly with a small sample size and inadequate study design. We recommend conducting prospective clinical studies with adequate methodology to address the question of whether or not oxygen therapy should be used to treat pneumothorax, regardless of the presence or absence of hypoxemia.