While early work on HMGB1 demonstrated its role as a late mediator of sepsis (10), more recently HMGB1 has been implicated as a putative danger signal involved in the pathogenesis of a variety of non-infectious inflammatory conditions including autoimmunity, cancer, trauma, and hemorrhagic shock, and ischemia-reperfusion injury. Furthermore, it has been studied in a number of organ systems including liver, heart, pancreas, brain, bone, and kidney. In addition to these studies highlighting the pro-inflammatory effects of HMGB1 in in vivo models of multiple diseases, there is emerging evidence to suggest that HMGB-1 can participate in tissue repair and remodeling as well as preconditioning; all of which are increasingly being recognized as important capacities of danger signals.