To describe the physiologic mechanisms of ventilator-induced lung injury and to define the major ventilator and host-dependent risk factors that contribute to such injury. Basic science and clinical studies related to ventilator-induced barotrauma and lung pathophysiology. Emphasis on controlled, experimental studies and clinical studies related to specific mechanisms. Preference given to studies with quantitative end-points to assess damage and causal relationships. Related studies are integrated to obtain basic mechanisms of damage where possible. Ventilation with high tidal volumes can increase vascular filtration pressures; produce stress fractures of capillary endothelium, epithelium, and basement membrane; and cause lung rupture. Mechanical damage leads to leakage of fluid, protein, and blood into tissue and air spaces or leakage of air into tissue spaces. This process is followed by an inflammatory response and possibly a reduced defense against infection. Predisposing factors for lung injury are high peak inspiratory volumes and pressures, a high mean airway pressure, structural immaturity of lung and chest wall, surfactant insufficiency or inactivation, and preexisting ing disease. Damage can be minimized by preventing overdistention of functional lung units during therapeutic ventilation. (Crit Care Med 1993; 21:131–143)