The acute respiratory distress syndrome (ARDS) is a clinical syndrome with primarily supportive management options. Despite extensive basic and clinical investigations, multiple pharmacological and nonpharmacological modalities have been unsuccessful in decreasing mortality. Nonetheless, these efforts have substantially heightened our understanding of ARDS pathophysiology. Investigators continue to create new and more complex therapeutic strategies that may have significant clinical impact. Several pharmacological agents for ARDS are in development and have shown either great promise or are at most, under phase II evaluation. The order in which therapeutic options are presented in this review highlights therapeutic options other than the anti-inflammatory approach. In addition to the anti-inflammatory category, vasodilators, surfactant therapy, immunonutrition and partial liquid ventilation are all being evaluated. Within the anti-inflammatory category. new mechanistic approaches include the 'anti-inflammatory nature' of interleukin-10, the inhibitory aspects of lysophosphatidic acid on endothelial cell permeability, and the use of recombinant human anti-coagulant proteins (activated protein C and tissue factor pathway inhibitor) to reduce the inflammatory cycle that contributes to microvascular thrombi. Previous work with surfactant in ARDS had its limitations, however, these trials were of sufficient success to spawn 2 new synthetic compounds. These new synthetic surfactants incorporate mixtures of phosphatidylcholine and phosphatidylglycerol (the key phospholipids within endogenous surfactant) and either recombinant surfactant protein C or an analogue of surfactant protein B. Recently, the ARDS Network's low tidal volume study has broken the cycle of decades of negative ARDS trials and demonstrated an improvement in mortality. Through better mechanistic approach and study design, investigator compliance with exclusion criteria, and better understanding of the complexities of patient management, the next pharmacological ARDS trials will hopefully be successful and lead to further reductions in patient mortality.