Mechanical ventilation is an indispensable tool in the management of respiratory and ventilatory failure. However, ventilation per se may also initiate or exacerbate lung injury, contributing to patient morbidity and mortality. In this review, we examine the current mechanisms of ventilator-induced injury including those that primarily involve physical disruption of the lung, as well as those more recently described that involve cell- and inflammatory-mediator-induced injury. The latter have received attention of late because of the possible systemic sequelae such as multiple system organ failure, the primary cause of death of patients with acute respiratory distress syndrome. Although much remains to be elucidated about the mechanisms of ventilator-induced injury, it is hoped that novel approaches addressing both the physiologic as well as molecular effects of ventilation will lead to innovative therapeutic approaches that improve patient outcome.