Acute respiratory distress syndrome (ARDS) affects some 10% to 15% of ICU patients and is associated with mortality rates of 40% to 50%. Although ARDS is the most severe form of acute respiratory failure, refractory hypoxia is an uncommon cause of death in these patients. The majority of patients who have ARDS die from multiple-organ dysfunction syndrome (MODS), and ARDS should, therefore, be seen as a systemic disease. Improved understanding of the systemic factors involved in the development and evolution of ARDS and MODS should facilitate the development of new therapeutic agents that will improve outcomes in these patients.