Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause substantial morbidity and mortality despite our improved understanding of lung injury, advancements in the application of lung-protective ventilation, and strategies to prevent ventilator-induced lung injury. Severe refractory hypoxemia may develop in a subset of patients with severe ARDS. We review several approaches referred to as "rescue" therapies for severe hypoxemia, including lung-recruitment maneuvers, ventilation modes, prone positioning, inhaled vasodilator therapy, and the use of extracorporeal membrane oxygenation. Each shows evidence for improving oxygenation, though each has associated risks, and no single therapy has proven superior in the management of severe hypoxemia. Importantly, increased survival with these strategies has not been clearly established.