Mechanical ventilation is life sustaining and is the standard therapy for acute respiratory failure. The 16th century anatomist Vesalius is often credited for the earliest account of positive-pressure ventilation. In his work De humani corporis fabrica (On the Fabric of the Human Body), he described how an animal could be resuscitated by blowing into a reed inserted into a hole in its trachea. Although positive pressure ventilation using bellows was first used for drowning victims in the 1700s, there were soon concerns that such therapy could in fact be harmful to the lungs. In 1827, Leroy d'Etoille condemned bellows ventilation after discovering that it could lead to emphysema and tension pneumothoraces. Subsequently, positive pressure ventilation would be virtually abandoned for over 100 years. Despite this early concern about the potential for harm from mechanical ventilation, it is only in the last one to two decades that research into so-called ventilator-induced lung injury (VILI) has blossomed. Indeed, although initial studies have focused on which ventilatory parameters are associated with the most (or least) harm, there has been an explosion of research in the last 5 years attempting to delineate the basic cellular mechanisms by which mechanical ventilation injures the lung. Recently, there has been exciting evidence to suggest that lung injury induced by mechanical ventilation may have important systemic consequences, including multi-organ dysfunction. Lastly and most importantly, there is accumulating data from clinical trials in humans that ventilatory strategies designed to avoid VILI can in fact save lives.