Mechanical ventilation is used to sustain life in patients with acute respiratory failure. A major concern in mechanically ventilated patients is the risk of ventilator-induced lung injury, which is partially prevented by lung-protective ventilation. Spontaneously breathing, nonintubated patients with acute respiratory failure may have a high respiratory drive and breathe with large tidal volumes and potentially injurious transpulmonary pressure swings. In patients with existing lung injury, regional forces generated by the respiratory muscles may lead to injurious effects on a regional level. In addition, the increase in transmural pulmonary vascular pressure swings caused by inspiratory effort may worsen vascular leakage. Recent data suggest that these patients may develop lung injury that is similar to the ventilator-induced lung injury observed in mechanically ventilated patients. As such, we argue that application of a lung-protective ventilation, today best applied with sedation and endotracheal intubation, might be considered a prophylactic therapy, rather than just a supportive therapy, to minimize the progression of lung injury from a form of patient self-inflicted lung injury. This has important implications for the management of these patients.