Activation of the coagulation system frequently accompanies systemic inflammatory states and is an almost invariable consequence of septic shock. The simultaneous activation of the innate immune response and the coagulation system after injury is a phylogenetically ancient, adaptive response that can be traced back to the early stages of eukaryotic evolution. Most invertebrate species lack differentiated phagocytic cells and platelets. They possess a common cellular and humoral pathway of inflammation and clotting after a breach in their internal milieu by either trauma or infection. The close linkage between clotting and inflammation has been preserved throughout vertebrate evolution and is readily demonstrable in human physiologic responses to a variety of potentially injurious stimuli. The same proinflammatory stimuli that activate the human clotting cascade also activate the phagocytic effector cells (neutrophils, monocytes, and macrophages). The complex and highly integrated linkage between systemic inflammation and coagulation are reviewed in this article.