Mesenchymal stem cells (MSCs) are widely used for their immunomodulatory properties in treating inflammatory diseases. However, recent studies challenge the notion that MSCs are "immune privileged," suggesting they may not be completely immune-privileged and can be rejected by the immune system. Despite this, the efficacy of allogeneic MSCs compared to autologous ones remains unclear, and no definitive clinical advantage of autologous MSCs has been shown. MSCs may exert therapeutic effects through a "hit and run" mechanism, but protecting them from immune detection and prolonging their persistence in vivo could improve clinical outcomes. MSCs were first identified in bone marrow and are now known to originate from various tissues. Despite their potential, the exact definition of MSCs remains debated. MSCs have been shown to suppress immune responses by inhibiting T-cell proliferation and promoting regulatory T cells and M2 macrophages. However, their immunomodulatory properties are not solely dependent on their stem cell characteristics but also on their trophic and immunomodulatory functions. Clinical trials using MSCs have increased significantly, with many trials using allogeneic MSCs. These trials have shown some positive results, but the long-term efficacy and safety of MSC therapy remain under investigation. MSCs can be manipulated in culture to enhance their therapeutic potential, but their persistence in vivo is limited, leading to potential immune rejection. MSCs are not immune privileged, and their rejection by the immune system has been observed in various studies. This rejection can lead to immune responses and reduced therapeutic effectiveness. Strategies to improve MSC persistence include modifying the host or the MSCs themselves, such as using immunosuppressive drugs or modifying MSCs to reduce their immunogenicity. Despite challenges, MSC therapy continues to be explored for various diseases. However, the immune response to MSCs and the need for improved strategies to enhance their persistence and efficacy remain critical areas of research. The future of MSC therapy may involve better understanding of their mechanisms, improved patient selection, and the development of more effective therapies that avoid immune rejection.Mesenchymal stem cells (MSCs) are widely used for their immunomodulatory properties in treating inflammatory diseases. However, recent studies challenge the notion that MSCs are "immune privileged," suggesting they may not be completely immune-privileged and can be rejected by the immune system. Despite this, the efficacy of allogeneic MSCs compared to autologous ones remains unclear, and no definitive clinical advantage of autologous MSCs has been shown. MSCs may exert therapeutic effects through a "hit and run" mechanism, but protecting them from immune detection and prolonging their persistence in vivo could improve clinical outcomes. MSCs were first identified in bone marrow and are now known to originate from various tissues. Despite their potential, the exact definition of MSCs remains debated. MSCs have been shown to suppress immune responses by inhibiting T-cell proliferation and promoting regulatory T cells and M2 macrophages. However, their immunomodulatory properties are not solely dependent on their stem cell characteristics but also on their trophic and immunomodulatory functions. Clinical trials using MSCs have increased significantly, with many trials using allogeneic MSCs. These trials have shown some positive results, but the long-term efficacy and safety of MSC therapy remain under investigation. MSCs can be manipulated in culture to enhance their therapeutic potential, but their persistence in vivo is limited, leading to potential immune rejection. MSCs are not immune privileged, and their rejection by the immune system has been observed in various studies. This rejection can lead to immune responses and reduced therapeutic effectiveness. Strategies to improve MSC persistence include modifying the host or the MSCs themselves, such as using immunosuppressive drugs or modifying MSCs to reduce their immunogenicity. Despite challenges, MSC therapy continues to be explored for various diseases. However, the immune response to MSCs and the need for improved strategies to enhance their persistence and efficacy remain critical areas of research. The future of MSC therapy may involve better understanding of their mechanisms, improved patient selection, and the development of more effective therapies that avoid immune rejection.