The treatment of respiratory failure requiring mechanical ventilation has advanced significantly over the last 20 years. The goal of therapy in patients with acute respiratory distress syndrome should be to optimize oxygenation while minimizing the risk of ventilator-induced lung injury and providing adequate ventilation. Appropriate use of ventilation modes and strategies, positive-end expiratory pressure levels, and recruitment maneuvers can improve oxygen delivery. Salvage therapies, such as prone positioning, inhaled epoprostenol and nitric oxide, and high-frequency oscillatory ventilation, have a well-established role in supportive management and are associated with improved oxygenation but not survival.