Publisher Summary The identification of tumor necrosis factor (TNF) as an early mediator of inflammation led to clinical therapies, which have improved the clinical course of many patients suffering from chronic inflammatory disease. Anti-TNF strategies have met with little success in diseases of acute systemic inflammation such as sepsis. It is hoped that the discovery and characterization of new cytokines, and pathological mechanisms will be important to the development of future therapies for inflammation. HMGB-1, first identified as a nuclear chromosomal protein, is now known as a proinflammatory cytokine that mediates delayed lethality in systemic inflammation. The discovery of HMGB-1 as a monocyte-derived, late-acting cytokine mediator of endotoxin lethality has initiated a new field of investigation for the development of experimental therapeutics. The downstream or “late” action of HMGB-1 is a marked departure from the early activities of TNF, and other classical proinflammatory cytokines, and has significant implications for understanding, and manipulating innate immune responses. Emerging data also suggest that therapeutics that inhibit HMGB-1 activity that are effective in preventing death in murine sepsis. The insights gained from these and other studies of HMGB-1 may lead to the development of new compounds which provide a wider therapeutic window for treatment of endotoxemia, sepsis, and septic shock.