HMGB1 (high-mobility group box 1 protein), also known as HMG1 or Amphoterin, is an intracellular protein that is regulated by multiple posttranslational modifications including acetylation, phosphorylation, and methylation. HMGB1 is released upon cell necrosis, apoptosis, and pyroptosis. It acts as a multifunctional alarmin that stimulates inflammation upon sterile or infectious insult. Receptors for HMGB1 include TLR2, TLR4, TLR9, Syndecan-3, Siglec-10, Integrin alpha M beta 2, CXCR4, TIM-3, and RAGE. It is implicated in the pathogenesis of a broad range of diseases including atherosclerosis, sepsis, cancer, neurodegenerative diseases, and autoimmunity.