High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types, is a necessary and sufficient mediator of inflammation during sterile and infection-associated responses. Elevated levels of HMGB1 in serum and tissues occur during sterile tissue injury and during infection, and targeting HMGB1 with antibodies or specific antagonists is protective in established preclinical inflammatory disease models including lethal endotoxemia or sepsis, collagen-induced arthritis, and ischemia-reperfusion induced tissue injury. Future advances in this field will stem from understanding the biological basis for the success of targeting HMGB1 to therapeutic improvement in the treatment of inflammation, infection and ischemia-reperfusion induced injury.