Progress in the treatment of acute respiratory distress syndrome(ARDS) has been slow, perhaps in part due to the heterogeneity in the biology underlying this syndrome. Open lung biopsy is a feasible approach to define various subcategories of underlying histology. In experienced hands, with careful selection of patients and close attention to details of critical care management,including mechanical ventilator settings, the procedure is safe even in patients with severe disease. However, further work is needed to define which patients, if any, experience a beneficial effect on outcome from this procedure. More research is needed on assessing efficacy of potential therapies within histologically defined subgroups. In the future, various biomarkers may be available to non-invasively classify ARDS patients from the standpoint of responsiveness to various therapies, such as glucocorticoids.