Despite a very large body of investigations, no effective pharmacological therapies have been found to cure acute lung injury. Hence, supportive care with mechanical ventilation remains the cornerstone of treatment. However, several experimental and clinical studies showed that mechanical ventilation, especially at high tidal volumes and pressures, can cause or aggravate ALI. Therefore, current clinical recommendations are developed with the aim of avoiding ventilator-induced lung injury (VILI) by limiting tidal volume and distending ventilatory pressure according to the results of the ARDS Network trial, which has been to date the only intervention that has showed success in decreasing mortality in patients with ALI/ARDS. In the past decade, a very large body of investigations has determined significant achievements on the pathophysiological knowledge of VILI. Therefore, new perspectives, which will be reviewed in this article, have been defined in terms of the efficiency and efficacy of recognizing, monitoring and treating VILI, which will eventually lead to further significant improvement of outcome in patients with ARDS.