Acute respiratory distress syndrome (ARDS) and acute lung injury are among the most frequent reasons for intensive care unit admission, accounting for approximately one-third of admissions. Mortality from ARDS has been estimated as high as 70% in some studies. Until recently, however, no targeted therapy had been found to improve patient outcome, including mortality. With the completion of the National Institutes of Health-sponsored Acute Respiratory Distress Syndrome Network low tidal volume study, clinicians now have convincing evidence that ventilation with tidal volumes lower than those conventionally used in this patient population reduces the relative risk of mortality by 21%. These data confirm the long-held suspicion that the role of mechanical ventilation for acute hypoxemic respiratory failure is more than supportive, in that mechanical ventilation can also actively contribute to lung injury. The mechanisms of the protective effects of low tidal volume ventilation in conjunction with positive end expiratory pressure are incompletely understood and are the focus of ongoing studies. The objective of the present article is to review the potential cellular mechanisms of lung injury attributable to mechanical ventilation in patients with ARDS and acute lung injury.