SUMMARY. The development of Intensive Care Units (ICUs) has been associated with the emergence of new iatrogenic diseases, which reflect a continuous “cross-talk” between various different noxious stimuli, the preserved through the evolution of homeostatic pathophysiological mechanisms and the treatment effects upon organ systems. One such disease or syndrome is the acute respiratory distress syndrome (ARDS). The majority of currently used definitions for ARDS, including that proposed by the American-European Consensus Conference (AECC), apply common diagnostic criteria for different pathological processes, resulting in misclassification of heterogeneous groups of patients within the same syndrome. This brief overview emphasizes the significant questions that were raised by investigators regarding the description of ARDS in the early years. Despite the progress that has been made, many methodological issues remain unresolved. The incorporation of new knowledge into appropriate definitions is a challenge, since the better understanding of the pathophysiology, and the design of clinical trials with positive results both depend on an appropriate description of ARDS. In this article, an attempt is made to emphasize the challenges of adopting a reliable and valid definition for ARDS, as indirectly proposed in the most recent relevant literature. Pneumon 2009, 22(3):223-229.