HMGB1 is a nonhistone nuclear protein that can serve as a cytokine and activate innate immunity. The translocation of this molecule from the inside to the outside of cells is a critical event in inflammation, occurring following activation of certain Toll-like receptors (TLRs) as well as during the course of apoptotic as well as necrotic cell death. Because the kinetics of HMGB1 release differs from that of a conventional cytokine, it provides a broader therapeutic window and may be an important new target of therapy for inflammatory, autoimmune, and infectious diseases.