Cells can die through two mechanisms: necrosis and apoptosis. Necrosis occurs in response to stimuli that cause cellular damage and result in the release of intracellular proteins, which stimulate the inflammatory response. Necrosis is associated with tissue damage and organ deterioration. Apoptosis is a programmed cell death during which the cellular membrane remains intact, but activated enzymes destroy the cell from within. Bustin discusses how the mobility of the nuclear protein high mobility group B1 (HMGB1) may be a key signal for determining whether certain cells undergo necrotic or apoptotic death. Necrosis may result when HMGB1 is released from the cells and stimulates the inflammatory response. HMGB1 appears to have extracellular signaling functions, such as stimulation of cell motility and tumor metastasis and activation of the cytokine signaling pathways. Through its action on the cytokine signaling targets, HMGB1 may be an important therapeutic target for diseases of cytokine excess, including septic shock.