Despite significant advances in the understanding of the complex pathophysiology, only a limited number of new treatments for acute lung injury (ALI) have emerged in the last 2 decades. This article discusses some of the challenges that remain in conducting clinical research in patients who have ALI and acute respiratory distress syndrome. New definitions that incorporate prognostic measures and reduce patient heterogeneity will allow more efficient enrollment of patients. Delineating outcomes attributable to the lung injury will improve the power of studies to detect significant treatment effects. Future collaborative studies will be needed to investigate longer-term clinical outcomes.