During mechanical ventilation the lungs are exposed to substantial physical forces. This is particularly true for patients with acute lung injury, where the applied pressures are two to three times higher than those present during normal breathing. The resultant overdistension activates specific mechanotransduction pathways, many of which activate inflammation pathways that might lead to (further) acute lung injury. In this article, we review evidence suggesting that pharmacological strategies can interfere with ventilator-induced lung injury at different stages of the inflammatory cascade: blockade of transcription factors, neutralization of chemokines, cytokines and neuropeptides, and inhibition of proteases. These findings provide rationale for the use of anti-inflammatory therapies to treat the side-effects of mechanical ventilation.