High mobility group box 1 (HMGB1) is a protein highly conserved among species, present in the nuclei (chromatin associated) and cytoplasm of virtually all cell types. In cytoplasm, HMGB1 is a critical regulator of autophagy, enhances cell survival and limits apoptosis; also, it acts as a chaperone reducing protein aggregation caused by heat or chemical stress.? HMGB1 is released to the extracellular milieu by inflammatory cells and by necrotic and apoptotic cells. Once released, it functions as an inflammatory cytokine; it is secreted by macrophages and monocytes as a late response to their treatment with LPS, TNFa, IL-1, or IFNg. Interestingly, the inflammatory activity of extracellular HMGB1 is dependent upon its redox state. The protein possesses three cysteine residues (C23, C45, C106). HMGB1 in reduce state (-SH) has chemotactic activity, whereas HMGB1 with a disulfide bond between C23 and C45 induces cytokine activity and activation of NF-κB. The fully oxidized form has no immune function; the protein loses its proinflammatory effect and the caspase-dependent apoptotic cell death activation. HMGB1 interacts with several molecules, such as IL-1β, RNA, DNA, LPS, lipoteichoic acid (LTA), and CXCL12. Thus HMGB1 develops greater proinflammatory activity through cytokine binding, and the chemotactic property is mediated by the binding to CXCL12. Extracellular HMGB1 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus, and cancer. Also, it has been associated to chronic pain and delayed gastric ulcer healing in mice.