Prone positioning has been known for decades to improve oxygenation in animals with acute lung injury and in most patients with acute respiratory distress syndrome (ARDS). The mechanisms of this improvement include a more uniform pleural-pressure gradient, a smaller volume of lung compressed by the heart, and more uniform and better-matched ventilation and perfusion. Prone positioning has an established niche as an intervention to improve gas exchange in patients with severe hypoxemia refractory to standard ventilatory manipulations. Because the lung may be more uniformly recruited and the stress of mechanical ventilation better distributed, prone positioning has also been proposed as a form of lung-protective ventilation. However, several randomized trials have failed to show improvements in clinical outcomes of ARDS patients, other than consistently better oxygenation. Because each of these trials had design problems or early termination, prone positioning remains a rescue therapy for patients with acute lung injury or ARDS.