HMGB1 first was implicated as an important endogenous signaling molecule in 1999 when Wang et al. described the cytokine activity of HMGB1 by identifying it as a late mediator of endotoxinrelated lethality in mice (10) . This study reported increased serum levels of HMGB1 from 8 to 32 h after endotoxin exposure, attenuation of lethality with delayed administration of an HMGB1 neutralizing antibody, and lethality with direct administration of HMGB1 (10) . This groundbreaking work sparked renewed interest in HMGB1 as an important component of the immune response.