Sepsis or its synonymously termed "SIRS (systemic inflammatory response syndrome)" is a common cause of individual morbidity and mortality in various clinical situations. In such conditions, high mobility group box-1 DNA binding protein (HMGB1), widely known as a nuclear structural protein, has been identified to act as a late mediator of delayed endotoxin lethality. Once released from necrotic damaged cells or secreted by activated monocytes/macrophage, it participates in the development of lethality and it activates downstream cytokine release. In this review, we describe herein the general features of sepsis focusing on the role of HMGB1 in the mechanism of development of systemic inflammation, and also introduce newly established therapeutic concept "Functional HMGB1 inhibition with thrombomodulin" against sepsis/SIRS/DIC.