Initially, the challenge of heterogeneity was daunting, but over time it became clear that it provided an opportunity to better elucidate the pathogenesis of ARDS and for the potential to develop targeted therapeutic interventions. Definitions for both ARDS and underlying risk factors (ie, sepsis) evolved,, and encompassed not only etiologies such as sepsis and trauma but the division of patients into those sustaining direct vs indirect lung injury. The impact of preexisting and comorbid conditions (including age, sex, ethnicity, diabetes, alcohol, obesity, kidney injury, smoking, and genetics), as well as features of clinical care such as mechanical ventilation, fluid management, and sedation, was identified. Furthermore, the site of measurements (ie, BAL vs blood) and the assay methods used to measure myriad biomarkers were also recognized as important contributors to the variations seen in the results. The initial translational and clinical studies were small and often included patients from only a single center, making it difficult to both identify and characterize the many heterogeneous patient populations that were included within the syndrome. However, large, well-characterized cohorts (including ones from the National Heart, Lung, and Blood Institute’s ARDS Network, the Mayo Clinic, and Vanderbilt) have been created over the last two decades, significantly increasing the power to both detect and analyze differences, identifying new and unique clinical phenotypes and biomarkers.