Injury to the lung parenchyma results in the acute respiratory distress syndrome (ARDS), which is a common and life-threatening cause of respiratory failure and mortality that develops after a variety of insults, including sepsis, multiple trauma, pneumonia, aspiration of gastric contents and severe burns. The pathogenesis of ARDS is complex with loss of the alveolar-capillary barrier and flooding of the airspaces with protein-rich fluid; injury to the alveolar epithelium; an influx of neutrophils and macrophages; and fibrin deposition as a result of activation of coagulation and inhibition of fibrinolysis. These changes develop over hours to a few days after the initiating event and often take days or weeks to resolve. Despite decades of research, there is only one therapy (low tidal volume ventilation) that has been shown to reduce mortality in ARDS. Further research into the pathogenesis of this devastating condition is crucial for the development of novel and specific therapies that target specific disease mechanisms. Unfortunately, no single animal model of ARDS replicates the complex pathophysiological changes seen in patients. This is a severe limitation in the study of ARDS and has impaired scientific and therapeutic progress in this field. Here, we discuss the primary features of this syndrome, highlight limitations of current animal models and suggest new approaches to investigate key components of pathogenesis. Hopefully, as new technologies and approaches emerge, barriers to scientific progress in ARDS will be overcome.