Despite significant advances in the management of trauma victims, sepsis and the ensuing multiple organ failure remain the leading causes of death in the surgical intensive care unit. Although much effort has been focused on the mediators released in large quantities following shock and sepsis, blockade of mediators such as proinflammatory cytokines has not yet resulted in a successful therapy. However, as more studies are forthcoming, the mechanisms responsible for cell and organ dysfunctions following trauma-hemorrhage and sepsis are becoming better understood, and promising new therapeutic approaches are currently being evaluated. In order to understand the precise mechanisms responsible for cellular dysfunction and consequently irreversible organ damage and multiple organ failure, it is important to correlate various pathophysiological changes with mediators and signal transduction pathways at the cellular and subcellular level. In this review we focus first on factors and mediators responsible for producing cell and organ dysfunctions, especially hepatocellular dysfunction, following trauma, hemorrhagic shock, and sepsis. The changes in signaling transduction pathways will also be discussed, specifically the role of mitogen-activated protein kinases, transcription factors, nitric oxide, heat shock proteins, and inflammatory cytokines in the development of cell and organ dysfunctions following trauma-hemorrhage and sepsis. Moreover, potential therapeutic approaches for improving cell and organ functions under adverse circulatory conditions are included.