High mobility group box 1 (HMGB1), a 30 kDa nuclear and cytosolic protein widely studied as a transcription factor and growth factor, has recently been identified as a cytokine mediator of lethal systemic inflammation (e.g. endotoxaemia and sepsis), arthritis and local inflammation. It is released by activated macrophages, and serum levels increase significantly during endotoxaemia, sepsis and arthritis with significant delayed kinetics in comparison with tumour necrosis factor (TNF) and interleukin-1beta. Recently identified biological activities of HMGB1 include activation of macrophages/monocytes to release proinflammatory cytokines, upregulation of endothelial adhesion molecules, stimulation of epithelial cell barrier failure, and mediation of fever and anorexia. Passive immunization with anti-HMGB1 antibodies confers significant protection against lethal endotoxaemia, sepsis, arthritis and lipopolysaccharide-induced acute lung injury, even when antibody administration is delayed until after the early TNF responses have resolved. Strategies to inhibit HMGB1 activity and release are being investigated in these and other preclinical models of acute and chronic inflammation.