Low-tidal-volume ventilation strategies are clearly beneficial in patients with acute lung injury and acute respiratory distress syndrome, but the optimal level of applied positive end-expiratory pressure (PEEP) is uncertain. In patients with high pleural pressure on conventional ventilator settings, under-inflation may lead to atelectasis, hypoxemia, and exacerbation of lung injury through "atelectrauma." In such patients, raising PEEP to maintain a positive transpulmonary pressure might improve aeration and oxygenation without causing over-distention. Conversely, in patients with low pleural pressure, maintaining a low PEEP would keep transpulmonary pressure low, avoiding over-distention and consequent "volutrauma." Thus, the currently recommended strategy of setting PEEP without regard to transpulmonary pressure is predicted to benefit some patients while harming others. Recently the use of esophageal manometry to identify the optimal ventilator settings, avoiding both under-inflation and over-inflation, was proposed. This method shows promise but awaits larger clinical trials to assess its impact on clinical outcomes.