PURPOSE OF REVIEW: To review the challenges and limitations of randomized clinical trials in acute respiratory distress syndrome, with special emphasis on those pertaining to ventilatory management. RECENT FINDINGS: Superbly executed randomized trials of ventilatory strategy have garnered deserved attention from the critical care community and yet have illustrated the limitations of our current approach to clinical research in this area. Inexact definitions, incomplete mechanistic understanding of complex pathophysiology, inappropriate outcome variables, diverse therapeutic environments, lengthy data acquisition time and ethical constraints on trial design limit the applicability of randomized control trial methodology to acute respiratory distress syndrome and acute lung injury. As yet, clinical practice does not seem to have been greatly impacted by the implications of completed randomized controlled trials per se. Recent issues, both ethical and interpretive, regarding control group participants have raised troubling and theoretically important issues that are yet to be fully resolved. SUMMARY: Without tighter definitions of the condition under treatment, more specific targets for interventions to act upon, stratification that recognizes key interactive elements, and cointerventions based on better mechanistic understanding, randomized controlled trials of new drugs, ventilatory strategy, and other management approaches in acute respiratory distress syndrome are likely to remain a blunt instrument for investigation. As valuable as they are for calling important therapeutic principles to attention and for helping to suggest general guidelines for care, the limitations of randomized controlled trials for treating the individual with acute respiratory distress syndrome must be acknowledged.