Severe hypoxemia is the hallmark of ARDS. However, unmanageable refractory hypoxemia fortunately is a rare occurrence in patients with ARDS and an infrequent cause of death in ARDS. However, in some patients, in spite of the application of lung protective ventilation with moderate to high levels of end-expiratory pressure (PEEP), refractory hypoxemia remains unresolved. When refractory hypoxemia persists, we first recommend the use of lung recruitment maneuvers and a decremental PEEP trial, if this does not resolve the refractory hypoxemia prone positioning should be attempted. The use of aerosolized pulmonary vasodilators can be used to buy time when these approaches fail as the patient is transitioned to extracorporeal membrane oxygenation. We also find that there is now sufficient evidence to recommend against the use of high frequency oscillation in the management of refractory hypoxemia.