Rationale: Lung injury due to ventilator results from un-physiological lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio). Objective: To determine whether the plateau pressure and the tidal volume are adequate surrogates for stress and strain. To quantify the stress to strain relationship in patients and control subjects. Methods: Nineteen post-surgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3) and 24 patients with ARDS (group 4) underwent a PEEP trial (5 and 15 cmH₂O) with 6, 8, 10 and 12 mL/kg tidal volume. Measurements and Main Results: plateau airway pressure, lung and chest wall elastances, lung stress and strain significantly increased from group 1 to 4 and increasing PEEP and tidal volume. Within each group a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range 0.33-0.95). Analogously for the same applied tidal volume the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore low or high tidal volume as 6 and 12 mL/kg could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio, i.e. specific lung elastance, was similar throughout the subgroups (13.4±3.4, 12.6±3.0, 14.4±3.6 and 13.5±4.1 cmH₂O, P=0.58) and did not change with PEEP and tidal volume. Conclusions: Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical Trial Registry Information: ID# NCT00143468 at www.clinicaltrials.gov