The Acute Respiratory Distress Syndrome Network clinical trial on ventilation of critically ill patients has drawn attention to the potential side effects of mechanical ventilation. Both clinical and basic research have demonstrated that injurious ventilation strategies can initiate or perpetuate local and systemic inflammatory responses. There are four principal mechanisms that can produce such a response. 1) Ventilation, especially with high ventilation pressures and zero positive end-expiratory pressure, can cause stress failure of the plasma membrane and of epithelial and endothelial barriers. Stress failure of the plasma membrane causes necrosis, which leads to liberation of both preformed inflammatory mediators and agents that stimulate other cells that are still intact to produce such mediators. 2) Stress failure of the barriers causes loss of compartmentalization with spread of mediators and bacteria throughout the body as a consequence. 3) Less injurious ventilation strategies that do not cause tissue destruction can elicit release of mediators by more specific mechanisms, presumably through activation of stretch-activated signaling cascades (mechanotransduction). 4) Ventilation with increasing positive pressures raises the pressure in the pulmonary circulation and thus vascular shear stress, both of which are known stimuli for endothelial cells. These different mechanisms should be taken into account in the design and the interpretation of studies on molecular mechanisms of ventilation-induced lung injury.