A preponderance of evidence exists implicating HMGB1 in the pathogenesis of ischemia/reperfusion injury (IRI) in multiple organ systems including kidney, brain, heart, and liver. Much of the seminal work identifying extracellular HMGB1 as an alarmin that initiates the inflammatory response resulting from IRI was performed using a model of partial warm hepatic IRI in mice. In this model, tissue levels of HMGB1 are elevated as early as 1 h following reperfusion (118) and continue to increase for up to 24 h following the insult. Furthermore, in this same model, neutralizing antibodies to HMGB1 ameliorate the damage resulting from IRI in a TLR4-dependent manner.