Since its description in 1967, the acute respiratory distress syndrome (ARDS) has become one of the most studied pathophysiological processes in intensive care units worldwide. The current state of knowledge about this severe illness and its associated mediators has come from the study of relevant animal models. In the mid-1970s, the development of the sheep model of ARDS and later, the porcine model, led to the discovery of a wide variety of inflammatory lipid mediators, cytokines, and proteases, to name but a few. Recognition of the presence of such highly toxic mediators associated with the development of ARDS has led to numerous potential targets for drug development toward therapeutic intervention. Through implementation of a standardized definition for ARDS and its less severe sibling acute lung injury (ALI), growth in patient-oriented research has been possible. Substantial numbers of new therapies have been brought forth and examined in recent years, many of which remain controversial. This article is a critical appraisal of the potential therapeutic options investigated in recent years for the management of ALI/ARDS.