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The American Thoracic Society/European Society for Intensive Care Medicine/Society of Critical Care Medicine guidelines on mechanical ventilation in adult patients with acute respiratory distress syndrome (ARDS) provide treatment recommendations derived from a thorough analysis of the clinical evidence on six clinical interventions. However, each of the recommendations contains areas of uncertainty and controversy, which may affect their appropriate clinical application.To provide a critical review of the experimental evidence surrounding the pathophysiology of ventilator-induced lung injury and to help clinicians apply the clinical recommendations to individual patients.We conducted a literature search and narrative review.A large number of experimental studies have been performed with the aim of improving understanding of the pathophysiological effects of mechanical ventilation. These studies have formed the basis for the design of many clinical trials. Translational research has fundamentally advanced understanding of the mechanisms of ventilator-induced lung injury, thus informing the design of interventions that improve survival in patients with ARDS.Because daily management of patients with ARDS presents the challenge of competing considerations, clinicians should consider the mechanism of ventilator-induced lung injury, as well as the rationale for interventions designed to mitigate it, when applying evidence-based recommendations at the bedside.