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Injury is a major cause of critical illness worldwide. Severely injured patients often require mechanical ventilation not only to manage primary respiratory failure but also as adjunct to manage other conditions. Injury induces fundamental changes in multiple organ systems which directly impact ventilator management; these changes are not shared by patients without concomitant tissue injury. In this article, we review the physiologic changes after injury and discuss the impact of injury on ventilator strategies and management. We also explore the special considerations in patients with traumatic brain injury, thermal injury, blast injury or bronchopleural fistula.