Mechanical ventilation is one of the most practiced interventions in the pediatric intensive care unit (PICU). Although unmistakable life-saving, it can also injury the lung, a process coined ventilator induced lung injury (VILI). To date, almost all of our knowledge VILI has been obtained from studies in adults or experimental studies mimicking the adult critical care situation. This leaves the question if VILI is of importance in the pediatric context. Pediatric clinical studies did not confirm an association between large tidal volume (Vt) and adverse outcome. In fact, the opposite has been shown. These same studies did show an association between high pressures and adverse outcome. Experimental data showed that the use of large, supraphysiologic Vt resulted in less inflammation and injury in pediatric animal models compared to adult models, suggesting an age-related susceptibility to VILI. However, the question whether or not there is an age-related susceptibility to VILI remains puzzling and unanswered. It is remarkable that one of the most practiced interventions such as pediatric MV is hardly supported by any scientific evidence but rather based on personal experience and data from adults. This signifies the need for clinical and experimental studies in order to better understand the use and effects of MV in pediatric patients with or without lung injury.