Ventilatory management of acute respiratory distress syndrome has evolved significantly in the last few decades. The aims have shifted from optimal gas transfer without concern for iatrogenic risks to adequate gas transfer while minimizing lung injury. This change in focus, along with improved ventilator and multiorgan system management, has resulted in a significant improvement in patient outcomes. Despite this, a number of patients develop hypoxemic respiratory failure refractory to lung-protective ventilation (LPV). The intensivist then faces the dilemma of either persisting with LPV using adjuncts (neuromuscular blocking agents, prone positioning, recruitment maneuvers, inhaled nitric oxide, inhaled prostacyclin, steroids, and surfactant) or making a transition to rescue therapies such as high-frequency oscillatory ventilation (HFOV) and/or extracorporeal membrane oxygenation (ECMO) when both these modalities are at their disposal. The lack of quality evidence and potential harm reported in recent studies question the use of HFOV as a routine rescue option. Based on current literature, the role for venovenous (VV) ECMO is probably sequential as a salvage therapy to ensure ultraprotective ventilation in selected young patients with potentially reversible respiratory failure who fail LPV despite neuromuscular paralysis and prone ventilation. Given the risk profile and the economic impact, future research should identify the patients who benefit most from VV ECMO. These choices may be further influenced by the emerging novel extracorporeal carbon dioxide removal devices that can compliment LPV. Given the heterogeneity of acute respiratory distress syndrome, each of these modalities may play a role in an individual patient. Future studies comparing LPV, HFOV, and VV ECMO should not only focus on defining the patients who benefit most from each of these therapies but also consider long-term functional outcomes.