High mobility group box 1 (HMGB1), a mobile chromatin protein, passively leaks from necrotic cells and signals neighboring cells that tissue damage has occurred. Resting, non-activated inflammatory cells such as monocytes or macrophages contain HMGB1 in the nuclear compartment. When activated by lipopolysaccharide or inflammatory cytokines, they actively translocate the nuclear HMGB1 into the cytoplasm; HMGB1 is then exocytosed. At least one receptor for extracellular HMGB1 has been identified. HMGB1 acts as a mediator of systematic inflammation; it causes different cells to divide, migrate or elicit an immune response. Here, we give an abridged review of the cytokine activity of HMGB1, including its secretion mechanism, the putative signal transduction pathways, and its role in several inflammatory diseases. Finally, we cite a few examples in which therapeutic administration of HMGB1 antagonists rescued mice from lethal sepsis, arthritis and liver damage. The new findings of HMGB1 as a cytokine provide a better understanding of inflammatory diseases, establishing a clinically relevant therapeutic target that is significantly more efficient than other known cytokines.