There has been significant progress in the field of heart transplantation over the last 45 years. Although the role of adaptive immunity in heart allograft rejection has been extensively studied for decades, there is increasing evidence that suggests that the innate immune system also contributes to the development of heart allograft rejection. The high-mobility group box (HMGB) proteins, particularly HMGB1, are self-derived innate immune activators that have multiple functions in the regulation of immunity and inflammation. Recent discoveries have illustrated the close link between HMGB1 and heart allograft rejection. In this review, we summarize current knowledge of the function of HMGB1 as a ligand that can evoke inflammatory responses and ultimately cause rejection after heart transplantation.