Mechanical ventilation has been used to support acutely ill patients for several decades. But clinicians are aware that, despite the life-saving potential of this assistance, it has several potential drawbacks and complications. A State of the Art review published several years ago in the American Review of Respiratory Disease recapitulated these complications (1). The present review focuses on what has recently emerged as one of the most serious potential complications of mechanical ventilation, ventilation-induced lung injury (VILI). VILI was, for years, synonymous with clinical barotrauma, the leakage of air due to disruption of the airspace wall. The extra-alveolar accumulation of air causes several manifestations (2), of which the most threatening is tension pneumothorax. The adverse consequences of these macroscopic events are usually immediately obvious, and this form of barotrauma has been the subject of clinical studies and the remarkable experimental studies of Macklin and Macklin (3). It is only very recently that the possibility that more subtle physiologic and morphologic alterations may occur during mechanical ventilation has been recognized. This form of injury is now a major preoccupation of most physicians caring for patients needing ventilatory support. Although several fundamental experimental studies were published before 1975, it was only 10 yr later that renewed interest in this subject stimulated the major research effort which has considerably expanded our knowledge. Unlike the classic forms of barotrauma (ie, extra-alveolar air), our knowledge of these alterations has come only from experimental studies. Alterations in lung fluid balance, increases in endothelial and epithelial permeability, and severe tissue damage have been seen following mechanical ventilation in animals. The macroscopic and even microscopic damage observed in VILI (4–6) is not specific. It closely resembles that observed in other forms of experimental acute lung injury (7–9). More importantly, it does not fundamentally differ from the diffuse alveolar damage observed during human acute respiratory distress syndrome (10). Thus, were VILI to occur in humans, it would be indistinguishable from most of the initial acute offending processes that lead to respiratory failure and the need for ventilator assistance. The possibility that mechanical ventilation can actually worsen acute lung disease is now widely accepted (11), despite the lack of a clear demonstration of a clinical equivalent of the experimental observations. Any demonstration of superimposed VILI during the course of human acute respiratory distress syndrome may be illusive. Thus, this concept derived from animal studies has resulted in complete reassessment of the use of mechanical ventilation for patients with acute lung diseases and underlies current trends in the clinical practice of mechanical ventilation (12). Indeed, the current orientation is to emphasize the potential importance of easing the stress on acutely injured lungs by using modes of ventilation that limit the pressure and volume of gas delivered to the lungs (13–18).