High-mobility group box 1 protein (HMGB1) (also known as amphoterin or HMG1) was originally defined as a non-histone nucleosomal protein that is important for the regulation of transcription. It is a 215 amino-acid protein, encoded on chromosome 13q12, which is highly conserved between species (99% species homology between rodents and humans). HMGB1 contains two internal repeats of positively charged domains, the A-and B-Box, in the N terminus, and a negatively charged COOH terminus ( Figure 1 ). The two boxes bind to the minor groove of chromatin, thus modifying DNA architecture. 1 This facilitates the binding of regulatory protein complexes to DNA such as V(D)J recombinases 2 and p53-p73 transcriptional complexes. [3] [4] [5] In its resting state, the acidic tail of HMGB1 interacts with specific residues in the A-Box and B-Box, forming an extended and flexible segment, shielding them from other interactions that might occur before HMGB1 binds DNA. 6 HMGB1 likely has a role in DNA repair and replication. HMGB1 overexpression, which is observed in many tumors, accelerates cell cycle progression, and recent data suggest that endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival 7 and that HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. 8 The discovery by Kevin J Tracey et al. (1999) in a mouse model of endotoxaemia that lipopolysaccharide (LPS)activated macrophages release HMGB1, but later than secretion of the pro-inflammatory cytokines TNF-a and interleukin 1 (IL-1), and that protection against endotoxin lethality could be obtained by administration of anti-HMGB1 antibodies 9 has revealed that HMGB1 is a proinflammatory mediator able to alert the immune system to tissue damage and to trigger an immediate response. The term 'alarmin' has been proposed to differentiate the endogenous molecules that are very rapidly released or produced in response to microbial infection or tissue injury, and act as potent effectors of innate defense. 10 Alarmins have antimicrobial, enzymatic or chromatin-binding activities and they share common features, including their rapid passive release from necrotic cells or secretion from cells of the innate immune system (macrophages, natural killer (NK) cells) in response to infection, they bind to TLRs and receptors of antigen-presenting cells such as DCs, thus promoting adaptive immunity, and they are involved in the reconstruction of tissues destroyed secondary to inflammation. 11 Based on these criteria, a list of putative alarmins has been proposed, including the defensins, eosinophil-derived neurotoxin, thymosins, annexins, HSPs, or IL-1a. 12 HMGB1 remarkably fulfills these criteria and it is probably the best-characterized alarmin. The crucial role of HMGB1 not only in response to infection, injury and inflammation, but also its pathological effects in many diseases have recently challenged important questions regarding its biological activities and pathological effects.