Management of patients with acute lung injury (ALI) rests on achieving a balance between the gas exchanging benefits of mechanical ventilation and the exacerbation of tissue damage in the form of ventilator-induced lung injury (VILI). Optimizing this balance requires an injury cost function relating injury progression to the measurable pressures, flows, and volumes delivered during mechanical ventilation. With this in mind, we mechanically ventilated naive, anesthetized, paralyzed mice for 4 h using either a low or high tidal volume (Vt) with either moderate or zero positive end-expiratory pressure (PEEP). The derecruitability of the lung was assessed every 15 min in terms of the degree of increase in lung elastance occurring over 3 min following a recruitment maneuver. Mice could be safely ventilated for 4 h with either a high Vt or zero PEEP, but when both conditions were applied simultaneously the lung became increasingly unstable, demonstrating worsening injury. We were able to mimic these data using a computational model of dynamic recruitment and derecruitment that simulates the effects of progressively increasing surface tension at the air-liquid interface, suggesting that the VILI in our animal model progressed via a vicious cycle of alveolar leak, degradation of surfactant function, and increasing tissue stress. We thus propose that the task of ventilating the injured lung is usefully understood in terms of the Vt-PEEP plane. Within this plane, non-injurious combinations of Vt and PEEP lie within a "safe region", the boundaries of which shrink as VILI develops.