Major surgical procedures induce a systemic inflammatory response syndrome (SIRS) characterized by the overproduction of proinflammatory cytokines, which induces excessive stress and may trigger postoperative complications. This has prompted the hypothesis that drugs which relieve SIRS might improve the postoperative course of major surgery. One of the most promising targets for these drugs is high-mobility-group box chromosomal protein 1 (HMGB1). In 1999, HMGB1 was found to be a key late mediator of sepsis. It is now known to be associated with various kinds of acute and chronic inflammation, and is recognized as one of the most important danger signals in stress response. In this article, we present the latest information about HMGB1 and discuss its promise as a novel target for modulating stress response.