High mobility group box 1 (HMGB1) presents in almost all somatic cells as a component of the cell nucleus. It is necessary for transcription regulation during cell development. Recent studies indicate that extracellular HMGB1, coming from necrotic cells or activated immune cells, triggers inflammatory response whereas intracellular HMGB1 controls the balance between autophagy and apoptosis. In addition, reduced HMGB1 can effectively mediate tissue regeneration. HMGB1, therefore, is regarded as a therapeutic target for inflammatory diseases. In this review, we summarized and discussed the immunomodulatory effect of HMGB1.