Sequential organ failure after multiple trauma emerges from a whole-body inflammatory process which develops as a complex host defense response to hypovolemic shock/resuscitation and traumatic tissue injury. Successful prevention and treatment involves exact assessment of inflicted damage and profound knowledge of the different stages of posttraumatic immune alterations. Local release of potent inflammatory mediators (cytokines, complement, arachidonic acid derivatives, reactive oxygen metabolites) primarily induces a repair process. However, massive soft tissue and bone injury, follow-up surgery, infections and blood transfusions trigger a systemic spill over of these mediators orchestrating a generalized inflammatory response (Systemic Inflammatory Response Syndrome, SIRS). Diffuse capillary leakage and microcirculatory disorder prepare cellular dysfunction. Secondary severe immune defects support septic complications which maintain an autodestructive process. Therapeutical advances depend on the analysis of local and time-dependent expression of relevant inflammatory mediators and cellular signalling systems.