Regulatory T cells (Tregs)—discovered by Shimon Sakaguchi, Mary Brunkow, and Fred Ramsdell, who were awarded the 2025 Nobel Prize—are central to inducing immune tolerance and preventing organ transplant rejection. These CD4⁺FoxP3⁺ cells suppress alloimmune responses through multiple mechanisms (IL-10, TGF-β secretion; CTLA-4–mediated dendritic cell modulation; IL-2 consumption; cytotoxic effects on effector T cells). Clinically, higher Treg levels correlate with better graft survival and fewer rejection episodes. Early-phase trials in kidney and liver transplantation show that adoptive Treg infusions are safe, reduce acute rejection, and allow lowering of toxic immunosuppressive drugs. Approaches include polyclonal Tregs, donor-specific Tregs (darTregs), low-dose IL-2 to expand Tregs in vivo, and cutting-edge CAR-engineered Tregs for precise graft targeting. Key challenges remain—maintaining Treg stability and specificity, avoiding off-target immunosuppression, and overcoming complex cell manufacturing. Future directions focus on CAR/FOXP3-engineered “super Tregs,” orthogonal IL-2 systems for selective in vivo expansion, biomaterial-based delivery, and scalable Treg production from thymus or iPSCs. These advances aim to achieve durable, donor-specific tolerance with minimal lifelong immunosuppression—potentially transforming transplant care.