The experimental evidence that ventilator could injure lungs through the application of excessive end-inspiratory volumes and transpulmonary pressures has led to major changes in the clinical management of patients suffering from the acute respiratory distress syndrome (ARDS). The prevention of ventilator-induced lung injury has become one of the main goals of current ventilator strategies for patients with ARDS as well as for patients with normal lungs that require mechanical ventilation. Tidal volume reduction allowed for a reduction in mortality that confirmed the clinical relevance of ventilator-induced lung injury. In contrast, strategies for setting positive end-expiratory pressure (PEEP) have been proposed but the optimal PEEP level remains unsettled. Considerable efforts have been made within the last decades to try to develop new ventilator strategies as well as pharmacological and mechanical measures in order to prevent VILI and further improve the outcome of ARDS patients. This review will strive to describe seminal experimental and clinical studies that aimed at preventing the development of VILI.