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The objective of this study was to review known clinical predictors and biologic markers of adverse clinical outcomes in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) that might be used as selection criteria in clinical trials of novel therapies for ALI/ARDS.Published studies on clinical predictors and biologic markers of adverse outcomes in ALI/ARDS.In large epidemiologic studies, a number of clinical factors have been identified consistently as independent predictors of mortality in ALI/ARDS. These include age, comorbidities, including chronic liver disease and immunosuppression, severity of illness scores, and the degree of multisystem organ failure. Several biologic markers of mortality have also been identified in large studies, including von Willebrand factor antigen, surfactant protein D, protein C, plasminogen activator inhibitor-1, interleukins 6 and 8, and the TNF receptors. The Pao2/Fio2 ratio at the onset of ALI/ARDS does not predict clinical outcome but may be more useful after the first day of ALI/ARDS. A persistently low Pao2/Fio2 ratio is associated with worse outcomes and may be a marker of failure to respond to conventional therapy. Changes in IL-6, IL-8, TNF receptors, and SP-D over the first 3 days of ALI/ARDS are also associated with adverse clinical outcomes. The use of a combination of clinical factors and biologic markers is a promising strategy that needs to be prospectively validated.The design of clinical trials for new therapies for ALI and ARDS is a complex problem that ultimately will have a major impact on both trial outcome and generalizability. A number of clinical factors and biologic markers can be used to differentiate groups of patients at highest risk for adverse clinical outcomes. Whether enriching study populations with these sicker patients will increase or decrease the likelihood of a treatment effect for a given therapy is unknown.