General anesthesia and mechanical ventilation affect gas exchange, ventilation and pulmonary perfusion and there is an increasing body of evidence that mechanical ventilation itself promotes lung injury. Lung protective mechanical ventilation in patients suffering from acute lung injury or acute respiratory distress syndrome by means of reduced tidal volumes and limited plateau pressures has been shown to result in reduction of systemic inflammatory mediators, increased ventilator-free days and reduction in mortality. Experimental studies suggest that mechanical ventilation of uninjured lungs may also induce lung damage; however, the clinical relevance remains unknown. Human prospective studies comparing mechanical ventilation strategies during general anesthesia have shown inconsistent results with respect to inflammatory mediators. There is a lack of clinical evidence that lung protective ventilation strategies as used in patients with lung injury may improve clinical outcome of patients with uninjured lungs. The question of which ventilatory strategy will best protect normal human lungs remains unanswered.