Extract: Survival has always been a challenge in nature and fast adaptation is the key. To adapt to new situations during evolution, cells learned to reuse available molecules for different purposes. One example of a molecule recruited from an extant cellular pathway into new functions is the high mobility group box 1 (HMGB1) protein. Over the years, HMGB1 has been known by many names (amphoterin, differentiation enhancing factor, sulphoglucuronyl carbohydrate binding protein-1, p30) and relatively recently has been discovered to have a double identity from a functional point of view. When it resides in the nucleus, HMGB1 binds and bends the DNA helix facilitating the formation of protein complexes (multiple proteins binding to the same stretch of DNA) that regulate nuclear biochemical transactions. Once outside the cell it acts as a potent signal of inflammation, which is a fast response set in motion following injury or infection. The inflammatory reaction is mediated by the innate immune system, which constitutes the first line of defense to tissue damage and microbial agents. Processes like elimination of dead cells, protection against invading microorganisms and tissue repair intersect at the level of innate immunity. We will summarize recently published data that point towards HMGB1 as a common signal of tissue injury and infection used by the innate immune system, and highlight its involvement in disease.