The article discusses the immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) and their potential therapeutic applications. MSCs have been traditionally regarded as "immune privileged," suggesting they can be used for allogeneic transplantation without significant immune rejection. However, recent studies indicate that MSCs can elicit immune responses and be rejected, challenging the notion of their immune privilege. The authors review the historical context of MSC discovery, their nomenclature, and the challenges in defining their phenotype. They highlight the clinical trials using MSCs to treat various diseases, noting that most patients receive allogeneic MSCs, which raises concerns about immune rejection. The article also explores the mechanisms by which MSCs exert their immunomodulatory effects, including the production of extracellular vesicles, cytokines, and growth factors. It discusses the persistence of MSCs in vivo and the strategies to enhance their persistence, such as combining MSCs with anti-rejection drugs or modifying MSCs to reduce their immunogenicity. The authors emphasize the need to recognize the immunogenicity of MSCs and consider approaches to avoid allo-reactive antibodies, suggesting that a combination of strategies may be most effective in extending MSC persistence and improving therapeutic outcomes.The article discusses the immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) and their potential therapeutic applications. MSCs have been traditionally regarded as "immune privileged," suggesting they can be used for allogeneic transplantation without significant immune rejection. However, recent studies indicate that MSCs can elicit immune responses and be rejected, challenging the notion of their immune privilege. The authors review the historical context of MSC discovery, their nomenclature, and the challenges in defining their phenotype. They highlight the clinical trials using MSCs to treat various diseases, noting that most patients receive allogeneic MSCs, which raises concerns about immune rejection. The article also explores the mechanisms by which MSCs exert their immunomodulatory effects, including the production of extracellular vesicles, cytokines, and growth factors. It discusses the persistence of MSCs in vivo and the strategies to enhance their persistence, such as combining MSCs with anti-rejection drugs or modifying MSCs to reduce their immunogenicity. The authors emphasize the need to recognize the immunogenicity of MSCs and consider approaches to avoid allo-reactive antibodies, suggesting that a combination of strategies may be most effective in extending MSC persistence and improving therapeutic outcomes.