OBJECTIVE To evaluate the potential efficacy of pressure limitation with permissive hypercapnia in the treatment of acute respiratory failure/adult respiratory distress syndrome on the basis of current theories of ventilator-induced lung injury, potential complications of systemic hypercarbia, and available human outcome studies. METHODS Articles were identified through MEDLINE, reference citations of published data, and consultation with authorities in their respective fields. METHODS Animal model experimentation and human clinical trials were selected on the basis of whether they addressed the questions of pressure limitation with or without hypercapnia, the pathophysiologic effects of hypercapnia, or the concept of ventilator-induced parenchymal lung injury. Frequently cited references were preferentially included. METHODS Data were analyzed with particular emphasis on obtaining the following variables from the clinical studies: peak inspiratory pressures, tidal volumes, minute ventilation, and PCO2. Quantitative aspects of respiratory physiology were used to analyze the theoretical effects of permissive hypercapnia on ventilatory requirements in normal and injured lungs. RESULTS Extensive animal model data support the hypothesis that ventilator-driven alveolar overdistention can induce significant parenchymal lung injury. The heterogeneous nature of lung injury in adult respiratory distress syndrome, with its small physiologic lung volume, may render the lung susceptible to this type of injury through the use of conventional tidal volumes (10 to 15 mL/kg). Permissive hypercapnia is an approach whereby alveolar overdistention is minimized through either pressure or volume limitation, and the potential deleterious consequences of respiratory acidosis are accepted. Uncontrolled human trials of explicit or implicit permissive hypercapnia have demonstrated improved survival in comparison with models of predictive mortality. CONCLUSIONS Avoidance of alveolar overdistention through pressure or volume limitation has significant support based on animal models and computer simulation. Deleterious effects of the associated hypercarbia in severe lung injury do not appear to be a significant limiting factor in preliminary human clinical trials. Although current uncontrolled studies suggest benefit, controlled trials are urgently needed to confirm these findings before adoption of the treatment can be endorsed.