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Extracellular HMGB1 has been implicated in a wide range of conditions, from trauma and sepsis to epilepsy and lupus. As a result, this almost ubiquitous biomolecule is garnering increasing interest as a potential target for new therapeutics. In a recent review paper, Prof Ulf Andersson et al. summarized the latest advances in our understanding of the release, receptor interactions and functional consequences of extracellular HMGB1.