Mechanical ventilation provides life-sustaining support for most patients with acute lung injury and acute respiratory distress syndrome; however, traditional approaches to mechanical ventilation may cause ventilator-associated lung injury, which could exacerbate or perpetuate respiratory failure caused initially by conditions such as pneumonia, sepsis, and trauma. This article reviews the theory, laboratory data, and results of recent clinical trials that suggest that modified ventilator strategies can reduce ventilator-associated lung injury and improve clinical outcomes.