The article discusses the mechanisms by which mesenchymal stem cells (MSCs) avoid allogeneic rejection in both humans and animal models. MSCs are hypoimmunogenic, lacking MHC-II and costimulatory molecule expression. They also modulate T cell responses indirectly through dendritic cell (DC) modulation and directly by disrupting NK and CD8+ and CD4+ T cell function. Additionally, MSCs induce a suppressive local microenvironment through the production of prostaglandins, interleukin-10, and indoleamine 2,3-dioxygenase, which depletes tryptophan. The review compares these mechanisms to maternal tolerance of fetal allografts and immune evasion strategies used by tumor cells. The findings suggest that MSCs could be beneficial in regenerative medicine, but understanding the hierarchy of signals controlling immunosuppression is crucial for their application.The article discusses the mechanisms by which mesenchymal stem cells (MSCs) avoid allogeneic rejection in both humans and animal models. MSCs are hypoimmunogenic, lacking MHC-II and costimulatory molecule expression. They also modulate T cell responses indirectly through dendritic cell (DC) modulation and directly by disrupting NK and CD8+ and CD4+ T cell function. Additionally, MSCs induce a suppressive local microenvironment through the production of prostaglandins, interleukin-10, and indoleamine 2,3-dioxygenase, which depletes tryptophan. The review compares these mechanisms to maternal tolerance of fetal allografts and immune evasion strategies used by tumor cells. The findings suggest that MSCs could be beneficial in regenerative medicine, but understanding the hierarchy of signals controlling immunosuppression is crucial for their application.