Acute respiratory distress syndrome (ARDS) is a common and severe form of acute lung injury, resulting from both direct (eg, pneumonia) and indirect (eg, sepsis) pulmonary insults. It is a common cause of admission to the intensive care unit due to hypoxemic respiratory failure requiring mechanical ventilation, and is associated with significant morbidity and mortality. In some patients, ARDS leads to the development of life-threatening refractory hypoxemia. In these patients, physicians may consider a number of therapies (eg, recruitment maneuvers, prone positioning, inhaled nitric oxide, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation) to alleviate hypoxemia in patients unable to maintain reasonable oxygenation while being supported with conventional mechanical ventilation. Although these strategies have demonstrated improved oxygenation with their use, their impact on patient-important outcomes (eg, mortality) remains unproven. However, in the minority of patients with ARDS and refractory hypoxemia, institution of these therapies may be considered on a case-by-case basis. Future studies are needed to elucidate the efficacy of these therapies on outcomes in patients with severe ARDS and refractory hypoxemia.