High mobility group box protein 1 (HMGB1) has been shown to participate in acute inflammatory reactions, including acute lung injury and sepsis. There is also evidence that circulating levels of HMGB1 are increased after severe trauma and are associated with clinically important outcome parameters, including mortality. Recent studies demonstrated that HMGB1 itself has little or no proinflammatory activity, but is able to potentiate inflammatory responses through binding to mediators, such as endotoxin or cytokines. Important questions are to determine the binding partners for HMGB1 in the setting of severe injury and whether inhibition of interactions of HMGB1 and associated molecules with the cell surface can affect outcome after trauma.