Damage-associated molecular patterns (DAMPs), a term also known as alarmins coined by Walter G. Land, Seong, and Matzinger, are endogenous danger molecules that are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors (PRRs). One of the most well-known DAMPs is high mobility group box-1 (HMGB1), the name being such due to its very fast movement in gel electrophoresis. Importantly, HMGB1 has been shown to contribute to the pathogenesis of various diseases including myocardial ischemia/reperfusion injury, epilepsy, diabetes, multiple sclerosis, cancer, as well as hepatic steatosis, and fatty liver disease. There are three sections in the book. The first section is named HMGB1 and Cancer, including two chapters. One of the chapters in the first section is focused on HMGB1 in cancer therapy and managing COVID-19 infection, as well as multiple sclerosis. The second chapter in the first section is the crosstalk between cancer and myocardial ischemia/reperfusion injury (MIR) through HMGB1 via ferroptotic cell death. The second section is HMGB1 and metabolic interactions, consisting of two chapters. The first chapter is HMGB1 and inflammation in adipose tissue, resulting in insulin resistance and type 2 diabetes.The second chapter in the second section sums up recent data related to HMGB1 and liver injury, e.g., drug-induced liver injury, alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis, sepsis, and acute chronic liver failure, hepatocellular death through oxidative stress, inflammatory signaling, and autophagy in hepatocytes. The third section is about HMGB1 and neurodegenerative diseases. The section contains four chapters. The first chapter in the section evaluates HMGB1 and its antagonist in brain disorders, including epilepsy, headache, neuroimmunological disorders, neurodegenerative disorders, and stroke. The second chapter in the third section is about the role of HMGB1 on post-brain injury, including potential mechanisms and therapeutic opportunities as well. The third chapter in the third section evaluates the interaction of HMGB1 and Multiple sclerosis via TLR4/NF-κB signaling pathway, leading to the release of proinflammatory cytokines causing an inflammatory response. The last chapter in the third chapter aims to explain the effects of HMGB1 on Epilepsy.