Severe respiratory failure (including acute lung injury and acute respiratory distress syndrome) caused by 2009 H1N1 influenza infection has been reported worldwide. Refractory hypoxemia is a common finding in these patients and can be challenging to manage. This review focuses on nonventilatory strategies in the advanced treatment of severe respiratory failure and refractory hypoxemia such as that seen in patients with severe acute respiratory distress syndrome attributable to 2009 H1N1 influenza. Specific modalities covered include conservative fluid management, prone positioning, inhaled nitric oxide, inhaled vasodilatory prostaglandins, and extracorporeal membrane oxygenation and life support. Pharmacologic strategies (including steroids) investigated for the treatment of severe respiratory failure are also reviewed.