Purpose of Review <p>The primary objectives of this review were to assess the rate of immune rejection associated with previously conducted xenogeneic mesenchymal stem cell (MSC) transplantations and to identify the animal species involved in these studies.</p> Recent Findings <p>Gene knockout strategies represent a highly promising approach for cross-species transplantation, particularly in humans. This is crucial because the human body naturally produces various antibodies that can trigger immune rejection, affecting not only cellular and tissue grafts but also decellularized scaffolds. The articular microenvironment has emerged as an ideal target for MSC transplantation due to its unique immunoprivileged characteristics, notably a low infiltration of polymorphonuclear leukocytes.</p> Summary <p>Stem cells (SCs) are undifferentiated cells characterized by their self-renewal capacity and varying potentials to differentiate into distinct cell lineages. These intrinsic properties unlock a broad spectrum of therapeutic applications for SCs in both human and veterinary medicine. However, when cellular, tissue, or organ transplantation is performed in an allogeneic or xenogeneic setting, immune rejection remains a significant hurdle. This mechanism primarily involves human leukocyte antigen (HLA) molecules belonging to the major histocompatibility complex (MHC). SCs, in turn, are considered immunologically privileged due to their low baseline surface expression of MHC class II and HLA-DR molecules. Such features may provide a crucial advantage for the application of xenogeneic SCs in treating various pathologies. This study reviewed research outcomes regarding SCs and xenotransplantation by systematically searching the SciELO and PUBMED databases for articles published between 2003 and 2023, finding that in 80% of the documented cases, there were no clinical signs of rejection. Furthermore, 80% of the targeted pathologies affected the musculoskeletal system, with studies encompassing five species: human, equine, canine, murine, and bovine. The majority of the researchers (60%) performed mesenchymal stem cell (MSC) transplantation, whereas 20% utilized hematopoietic stem cells (HSCs). The infused SC dosage varied depending on the species involved. Overall, a limited number of studies bridging SCs and xenotransplantation have been conducted over the past two decades. Additional rigorous studies are suggested by the authors so that the clinical efficacy of this therapeutic approach can be conclusively proven.</p>