© Cambridge University Press 2007 and 2009. Despite improvements in critical care medicine, trauma continues to be one of the leading causes of death in developed countries. Severe trauma induces an elevation of circulating inflammatory cytokines (1), upregulation of vasoconstrictors (2), and alteration in coagulation cascade (3). It also leads to an impairment of endothelial function and circulatory alterations in major organs, which can lead to multiple organ dysfunction syndrome (MODS) (4) and eventually to multiple organ failure (MOF). In this regard, numerous studies have focused on examining the mechanisms of endothelial dysfunction following trauma so that effective treatment strategies may be developed. In the literature, a tendency exists to group trauma and massive hemorrhage under the same heading. Indeed, massive hemorrhage rarely occurs (with the exception of aortic aneurysm) in the absence of trauma (experimental models notwithstanding), and severe trauma usually is accompanied by hemorrhage. However, it is important to recognize that simple hemorrhage per se or tissue trauma without massive blood loss may trigger distinct pathways and lead to differences in host response. Severe hemorrhage (with and without tissue trauma) or severe tissue trauma (with or without massive blood loss) eventually leads to the activation of the same final pathways that lead to organ dysfunction and eventual failure, if the process is not controlled and corrected in due course. Furthermore, the site of injury (e.g., brain, thoracic, abdominal, and extremity) and the modality of resuscitation (e.g., massive blood transfusion versus resuscitation by Ringer's lactate) also may result in different host response. In this regard, allogeneic blood transfusion clearly will elicit immunosuppression and produce an entirely different response than resuscitation with Ringer's lactate. Furthermore, additional complicating issues include whether the injury is internal or external, penetrating or blunt.