Acute lung injury (ALI), a major cause of morbidity and mortality worldwide, remains a challenge for clinicians and scientists despite decades of investigation. Although substantial progress has been made in understanding the pathogenesis of ALI and, recently, mortality has been decreased by reevaluating the approach to mechanical ventilation in patients with the syndrome, there are still major voids in our knowledge. To date, we are able to predict neither who will acquire ALI nor who will survive, and there are not yet any beneficial pharmacologic interventions. Within the last decade, however, a number of factors have been identified that help to explain the apparent lack of progress and provide opportunities for the development of targeted therapeutic interventions. These include the recognition that the definition of the syndrome,1– patient variables, and environmental interactions are all critically important in this syndrome. Not only do the incidence and outcome from ALI vary with specific risk factors including sepsis and trauma, and pulmonary vs nonpulmonary factors, but preexisting factors including age, gender, and race, and comorbid conditions such as diabetes and alcohol abuse also impact incidence and outcome.2–4 The tremendous heterogeneity that exists among patients at risk for and with ALI likely explains the apparent lack of benefit from any of the pharmacologic interventions that have been studied. In light of the significant differences in biomarkers in these various patient groups,5 it makes sense that one therapy is not likely to benefit all; rather, a new approach that allows for the development of targeted therapeutic interventions is more likely to be successful.