The article discusses the role of HMGB1 (high mobility group protein B1) in sterile inflammation and infection. HMGB1 is a nuclear protein that is actively or passively released during sterile injury or infection, activating innate immune responses. The discovery that HMGB1 mediates these responses has led to the understanding of its critical role at the intersection of host inflammatory responses to sterile and infectious threats. HMGB1 binds and signals through TLR4, leading to cytokine release and tissue damage. Experimental strategies targeting HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity, significantly reducing damage in models of sterile and infectious threats. The article reviews the progress in understanding HMGB1 biology and its therapeutic potential in inflammatory diseases caused by injury, ischemia, or infection. Key findings include the role of HMGB1 in endotoxemia, sepsis, gastrointestinal inflammation, pancreatitis, respiratory disorders, arthritis, hemorrhagic shock, cerebral ischemia, myocardial infarction, atherosclerosis, and transplantation. The article highlights the importance of targeting HMGB1 to modulate inflammatory responses and reduce tissue damage.The article discusses the role of HMGB1 (high mobility group protein B1) in sterile inflammation and infection. HMGB1 is a nuclear protein that is actively or passively released during sterile injury or infection, activating innate immune responses. The discovery that HMGB1 mediates these responses has led to the understanding of its critical role at the intersection of host inflammatory responses to sterile and infectious threats. HMGB1 binds and signals through TLR4, leading to cytokine release and tissue damage. Experimental strategies targeting HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity, significantly reducing damage in models of sterile and infectious threats. The article reviews the progress in understanding HMGB1 biology and its therapeutic potential in inflammatory diseases caused by injury, ischemia, or infection. Key findings include the role of HMGB1 in endotoxemia, sepsis, gastrointestinal inflammation, pancreatitis, respiratory disorders, arthritis, hemorrhagic shock, cerebral ischemia, myocardial infarction, atherosclerosis, and transplantation. The article highlights the importance of targeting HMGB1 to modulate inflammatory responses and reduce tissue damage.