Mechanical ventilation is a supportive lifesaving therapy that can potentially cause lung injury if periodic alveolar overdistension, or cyclic collapse, and reopening occur. The use of a low tidal volume with moderate to high positive end-expiratory pressure improves the survival of patients with acute lung injury and acute respiratory distress syndrome. Positioning the patient with the “good lung down” and using differential ventilation with selective positive end-expiratory pressure are the two currently accepted ventilatory strategies to be applied in patients with severe unilateral lung injury. However, both have serious limitations in clinical practice. Lung injury may be rather inhomogeneous—confined to one lung or preferentially distributed toward the dependent lung areas. In unilateral lung injury, ventilatory strategies that allow recruitment of injured lung and that avoid overdistension of uninjured lung parenchyma should be applied. Experimental studies have shown that the use of selective tracheal gas insufflation and partial liquid ventilation facilitates low tidal volume with appropriate gas exchange while reducing cyclic lung stretch and shear stresses. Further studies are needed to determine future applications of these therapies in humans.