Acute respiratory distress syndrome (ARDS) and ventilator induced lung injury (VILI) continue to challenge clinicians who care for the critically ill. Current research in ARDS has focused on ventilator strategies to improve the outcome for these patients. In this review, we emphasize the limitations of managing ventilators based on airway pressures alone. Specifically, basic pulmonary mechanics including chest wall compliance and transpulmonary pressure are reviewed. This review suggests that perturbations in chest wall compliance and transpulmonary pressure may explain the lack of efficacy observed in recent clinical trials of ventilator management. We present a method for estimating pleural and transpulmonary pressures from esophageal manometry. Quantifying these variables and individualizing ventilator management based on individual patient physiology may be useful to intensive care clinicians who treat patients with ARDS.