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Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation. There is increasing recognition of a condition termed ventilator-induced diaphragmatic dysfunction. The purpose of the present review is to present evidence that mechanical ventilation can itself be a cause of diaphragmatic dysfunction, to outline our current understanding of the cellular mechanisms responsible for this phenomenon, and to discuss the implications of recent research for future therapeutic strategies.Many critically ill patients demonstrate diaphragmatic weakness. A large body of evidence from animal models, and more limited data from humans, indicates that mechanical ventilation can cause muscle fiber injury and atrophy within the diaphragm. Current data support a complex underlying pathophysiology involving oxidative stress and the activation of several intracellular proteolytic pathways involved in degradation of the contractile apparatus. This includes the calpain, caspase, and ubiquitin–proteasome systems. In addition, there is a simultaneous downregulation of protein synthesis pathways. Studies in animal models suggest that future therapies may be able to specifically target these processes, whereas for the time being current preventive measures in humans are primarily based upon allowing persistent diaphragmatic activation during mechanical ventilation.Diaphragmatic dysfunction is common in mechanically ventilated patients and is a likely cause of weaning failure. Recently, there has been a great expansion in our knowledge of how mechanical ventilation can adversely affect diaphragmatic structure and function. Future studies need to better define the evolution and mechanistic basis for ventilator-induced diaphragmatic dysfunction in humans, in order to allow the development of mechanical ventilation strategies and pharmacologic agents that will decrease the incidence of ventilator-induced diaphragmatic dysfunction.