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Since its introduction into the management of the acute respiratory distress syndrome, mechanical ventilation has been so strongly interwoven with its side effects that it came to be considered as invariably dangerous. Over the decades, attention has shifted from gross barotrauma to volutrauma and, more recently, to atelectrauma and biotrauma. In this article, we describe the anatomical and physiologic framework in which ventilator-induced lung injury may occur. We address the concept of lung stress/strain as applied to the whole lung or specific pulmonary regions. We challenge some common beliefs, such as separately studying the dangerous effects of different tidal volumes (end inspiration) and end-expiratory positive pressures. Based on available data, we suggest that stress at rupture is only rarely reached and that high tidal volume induces ventilator-induced lung injury by augmenting the pressure heterogeneity at the interface between open and constantly closed units. We believe that ventilator-induced lung injury occurs only when a given threshold is exceeded; below this limit, mechanical ventilation is likely to be safe.