Two randomized controlled trials confirmed the existence of so-called ventilator-associated lung injury by showing reduced morbidity and mortality with the use of lower tidal volumes in patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). While guidelines now strongly advise using lower tidal volumes in ALI/ARDS patients, at present there are no widely agreed upon guidelines for setting tidal volumes in patients who do not suffer from ALI/ARDS. The literature was searched for clinical studies on lung-protective mechanical ventilation using lower tidal volumes in patients not suffering from ALI/ARDS. The best available evidence comes from large retrospective or observational studies which suggest a causal relation between the use of large tidal volumes and the development of lung injury. The inconsistent results from smaller randomized controlled trials, however, do not definitely support the use of lower tidal volumes. The association with potentially injurious ventilator settings, in particular large tidal volumes, suggests that additional lung injury in mechanically ventilated patients without ALI/ARDS is, in part, a preventable complication. Nevertheless, more prospective studies are needed to evaluate optimal ventilator management strategies for patients not suffering from ALI/ARDS.