Though well described even in ancient writings, the acute respiratory distress syndrome (ARDS) gained major medical attention with the availability of mechanical ventilation and establishment of intensive care units. In the 50 years since this beginning there have been remarkable advances in the understanding of the etiology, physiology, histology, and epidemiology of this often lethal complication of common human maladies. Until recently, improvements in outcome have mainly followed improvements in intensive care unit operation and their associated life support systems, and have not come through discoveries made in the course of prospective randomized trials. In spite of the remarkable increase in research focused on ARDS, there remain a large number of unanswered clinical questions that are potentially extremely important with regard to short-term morbidity as well as long-term outcome. The ARDS Clinical Trials Network study of tidal volume has proven that randomized trials in ARDS with positive results are possible even when using difficult primary outcome measures such as mortality or ventilator-free days. Therefore, the rich combination of new trial strategies, potential treatments, experienced investigators, and increasingly standardized routine care set the stage for rapid advances to be made in the short- and long-term outcomes of this devastating syndrome.