Despite recent advances in antibiotic therapy and intensive care, sepsis remains the most common cause of death in the intensive care units, claiming approximately 225000 victims annually in the USA alone. The pathogenesis of sepsis is attributable, at least in part, to dysregulated systemic inflammatory responses characterized by excessive accumulation of various proinflammatory cytokines. A ubiquitous nuclear protein, high mobility group box 1 (HMGB1), is released by activated macrophages/monocytes, and functions as a late mediator of lethal endotoxaemia and sepsis. First, circulating HMGB1 levels are elevated in a delayed fashion (after 16-32h) in endotoxaemic and septic animals. Second, administration of recombinant HMGB1 to mice recapitulates many clinical signs of sepsis, including fever, derangement of intestinal barrier function, lung injury and lethal multiple organ failure. Third, administration of anti-HMGB1 antibodies or inhibitors (e.g. ethyl pyruvate, nicotine, stearoyl lysophosphatidylcholine and Chinese herbs such as Angelica sinensis) protects mice against lethal endotoxaemia, and rescues mice from lethal experimental sepsis even when the first doses are given 24 hours after onset of sepsis. Taken together, these experimental data establish HMGB1 as a late mediator of lethal endotoxaemia and sepsis with a wider therapeutic window for the clinical management of lethal systemic inflammatory diseases.