Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage, for which the use of autologous donor cells has been preferred to avoid immune rejection. Recently, however, rodent as well as human mesenchymal stem cells have been reported to be uniquely immune-tolerant, in both in vitro and in vivo transplant models. In this review, we explore in detail the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as "universal donor cells" with fascinating clinical implications.