Multiple organ dysfunction syndrome (MODS) is the primary cause of death in patients admitted to ICUs. Despite the development of better resuscitation, more powerful antibiotics, and more sophisticated methods for organ support, our ability to rescue patients from established MODS has not improved significantly since the syndrome was first described two decades ago. Rapid advancements in molecular biology have begun to unravel some of the potential mechanisms behind the development of this syndrome, and have suggested many potential therapeutic approaches. To effectively use these new treatment options as they become available, it is necessary to have a clear understanding of how these therapies fit into the current theories on the pathophysiology of MODS. Thus, the goal of this article is to integrate what is new in our understanding of the development of MODS with current concepts regarding potential therapies of this complex and perplexing syndrome.