Many individuals are now surviving their injuries to face the consequences of an activated immunoinflammatory system and the complications of supportive therapy. The pulmonary system bears the force of this insult. An understanding of the epidemiology of acute respiratory failure, as well as a greater knowledge of the cellular and subcellular mechanisms by which pulmonary dysfunction occurs, has led to novel approaches to the management of acute respiratory failure. It also appears that lung injury is caused, or at least exacerbated, by iatrogenic insults, such as positive-pressure ventilation. The purpose of this review is to discuss the etiology and pathophysiology of acute respiratory failure following severe injury and the novel therapeutic approaches. A combination of immunomodulating and mechanical ventilation strategies will likely provide the most successful approach to reducing the morbidity and mortality associated with acute respiratory failure following injury.