High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by injured or damaged cells. Thus, serum and tissue levels of HMGB1 are elevated during infection, and especially during sepsis. Sepsis is a systemic inflammatory response to disease and the most severe complication of infections, and HMGB1 acts as a potent proinflammatory cytokine and is involved in delayed endotoxin lethality and sepsis. Furthermore, the targeting of HMGB1 with antibodies or specific antagonists has been found to have protective effects in established preclinical inflammatory disease models, including models of lethal endotoxemia and sepsis. In the present study, emerging evidence supporting the notion that extracellular HMGB1 acts as a proinflammatory danger signal is reviewed, and the potential therapeutic effects of a wide array of HMGB1 inhibitors agents in sepsis and ischemic injury are discussed.