Tissue regeneration is a well-orchestrated process that occurs after injury caused by disease, physical trauma or infection, among others, while tumorigenesis is often considered as pathologically misappropriated tissue regeneration. Both injured tissues and tumors release intracellular molecules, called Damage-Associated Molecular Patterns (DAMPs), which are essential for tissue healing and protection of the host. The Unit is particularly interested in HMGB1, a DAMP originally identified as a nuclear protein involved in chromatin dynamics, that also acts as a signal of tissue damage when extracellularly released. We demonstrated that alternative redox forms of HMGB1 orchestrate sequential physiological processes after tissue injury—signaling damage, triggering inflammation, and promoting regeneration. Of most direct utility, we generated a designer HMGB1 as a drug candidate to promote tissue repair without exacerbating inflammation.