High mobility group box 1 (HMGB1) is named for its electrophoretic mobility on pol‐ yacrylamide gels when it was first identified in calf thymus in 1973. HMGB1 plays a critical role in the stress response not only inside the cell as a DNA chaperone and cell death regulator, but also outside the cell as the prototypic damage-associated molecu‐ lar pattern molecule. The physiological and pathological role of HMGB1 in health and disease has been widely studied for years. In this chapter, we will focus on the release and function of HMGB1 in cell death types such as apoptosis, autophagy, and ne‐ crosis.