AbstractMediators play a key role in the development of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, and multiple organ failure of vital organs. In this short review, we update our knowledge on these mediator networks. First, we summarize the stimuli that occur during severe trauma (intraoperative stress), including polymorphonuclear neutrophil‐derived tissue‐damaging substances, complement activation products, and adherence molecules such as selectins. The gut in shock is discussed as an important intermediate step in the transition from noninfectious to infectious SIRS. Second, we describe the mediators, including cytokines, nitric oxide, phospholipase A2, platelet‐activating factor, and procoagulatory substances, that are released during sepsis. The release of mediators depends primarily on the severity of the trauma, shock, or sepsis and secondarily on the activation of the various cascades of mediators during posttraumatic/postoperative complications. The mediators are thus of decisive importance regarding the intensity of organ damage and the outcome.