Mechanical ventilation can produce lung physiological and morphological alterations termed ventilator-induced lung injury (VILI). Early experimental studies demonstrated that the main determinant of VILI is lung end-inspiratory volume. The clinical relevance of these experimental findings received resounding confirmation with the results of the acute respiratory distress syndrome (ARDS) Network study, which showed a 22% reduction in mortality in patients with the acute respiratory distress syndrome through a simple reduction in tidal volume. In contrast, the clinical relevance of low lung volume injury remains debated and the application of high positive end-expiratory pressure levels can contribute to lung overdistension and thus be deleterious. The significance of inflammatory alterations observed during VILI is debated and has not translated into clinical application. This review examines seminal experimental studies that led to our current understanding of VILI and contributed to the current recommendations in the respiratory support of ARDS patients.