The clinical relevance of experimental ventilator-induced lung injury has recently received a resounding illustration by the Acute Respiratory Distress Syndrome Network trial that showed a 22% reduction of mortality in patients with acute respiratory disease syndrome when lung mechanical stress was lessened by tidal volume reduction during mechanical ventilation. This clinical confirmation of the concept of ventilator-induced lung injury has also undisputedly substantiated the experimental observation that excessive tidal volume and/or end-inspiratory lung volume is the main determinant of ventilator-induced lung injury. More recently, attention has focused on the roles and implication in the pathogenesis of ventilator-induced lung injury of inflammatory cells and mediators that may be activated and released either in the alveolar space or in the systemic circulation because of the rupture of the alveolar-capillary barrier and on the cellular response to mechanical stress.