Patients with sepsis may require mechanical ventilation due to the acute respiratory distress syndrome (ARDS). It has become increasingly accepted that mechanical ventilation can contribute to lung injury in these patients. The modern concept of ventilator-induced lung injury is described in the context of alveolar over-distention (volutrauma), alveolar de-recruitment (atelectrauma), and biochemical injury and inflammation to the lung parenchyma (biotrauma). To avoid over-distention lung injury, the tidal volume should be set at 6 mL/kg predicted body weight and plateau pressure should be limited to 30 cm H2O. This has been shown to afford a survival benefit. Although setting positive end-expiratory pressure (PEEP) to zero is likely harmful during mechanical ventilation of patients with ARDS, evidence is lacking for a survival benefit if a high PEEP level is set compared with a modest level of PEEP. Although adjunctive measures such as recruitment maneuvers, prone position, and inhaled nitric oxide may improve oxygenation, evidence is lacking that these measures improve survival.