This review describes the current understanding of the lungs' response to deforming stress under conditions of both normal physiology and acute lung injury. Several limiting assumptions are needed to infer lung parenchymal stress and strain from airway pressure, volume, and flow data from mechanically ventilated patients with injured lungs. These assumptions include the effects of the chest wall on lung-surface pressure, its topographical distribution, and the effects of non-uniform tissue properties on local parenchymal stresses. ⋯ Understanding both the assumptions of lung mechanics and the scope of injury mechanisms operating during ARDS is necessary to interpret the results of clinical trials that inform prevailing ventilator-management guidelines. The implications issuing from these 3 topics inform a safer approach to setting and adjusting the ventilator to minimize the risk of ventilator-induced lung injury. This is enumerated in a 5-step approach that can be used to guide ventilator management of unstable patients with severe lung injury.