Human High-mobility group box 1 protein (HMGB1), previously known as HMG-1 or amphoterin, is a member of the high mobility group box family of non-histone chromosomal proteins. Human HMGB1 is expressed as a 30 kDa, 215 amino acid (a.a.) single chain polypeptide containing three domains: two N-terminal globular, 70 a.a. positively charged DNA-binding domains (HMG boxes A and B), and a negatively charged 30 a.a. HMGB1 binds DNA in a non-sequence specific manner and may act as a structural cofactor during gene transcription. Acetylation of HMGB1 results in its cytoplasmic localization and eventual secretion. HMGB1 can be secreted by multiple cell types, and it is also released upon cell necrosis, apoptosis, and pyroptosis. HMGB1 is widely recognized as a multifunctional alarmin that stimulates inflammation upon sterile or infectious insult. It is implicated in the pathogenesis of a broad range of diseases including atherosclerosis, sepsis, cancer, neurodegenerative diseases, and autoimmunity.