High-mobility group box 1 (HMGB1) was originally identified as a highly conserved nuclear DNA-binding protein that participates in DNA replication, repair and transcriptional regulation of gene expression. Although the nuclear role of HMGB1 is not quite understood, recent studies characterized the emerging role of extracellular HMGB1 as a prototypical danger signal that regulates inflammatory and repair responses. Under conditions of infection, injury and sterile inflammation, HMGB1 can be passively released from damaged cells or actively secreted from activated immune cells. Inflammasomes, large caspase-1-activating protein complexes, were recently shown to play a critical role in mediating the extracellular release of HMGB1 from activated and infected immune cells.