Groundbreaking research into the pathophysiology of the adult acute respiratory distress syndrome (ARDS) and the prevention of ventilator-induced lung injury has led to dramatic improvements in survival. Investigations over the last two decades have revolved around the development of rescue therapies that can be used for patients with severe ARDS and refractory hypoxemia. To date, the techniques of using high levels of positive end-expiratory pressure (PEEP), prompt institution of neuromuscular blockade, and early prolonged prone positioning have been shown to reduce mortality in patients with severe ARDS. PEEP titration using transpulmonary pressure estimations assisted by esophageal manometry has been shown to result in a substantial improvement in oxygenation. Extracorporeal membrane oxygenation (ECMO) has been used increasingly since the mid-2000s in part due to the H1N1 epidemic. A major randomized controlled trial conducted during this period showed a significant mortality benefit for patients with severe ARDS who were referred to a center with ECMO capabilities. The routine use of inhaled nitric oxide for patients with severe ARDS has not been shown to lead to more than a transient and limited improvement in oxygenation, which may hinder its use as a sole rescue therapy. Finally, recent studies have found that the routine use of high-frequency oscillatory ventilation in severe ARDS does not result in decreased mortality, although the technique has not been specifically investigated as rescue therapy for severe refractory hypoxemia.