Chimerism—the coexistence of donor and recipient hematopoietic cells—has become central to understanding and inducing immune tolerance in solid organ transplantation. Early work by Owen, Medawar, and later Starzl revealed that donor “passenger leukocytes” can persist as microchimerism in recipients, reshaping the once one-way host-versus-graft paradigm into a bidirectional model. Stable mixed chimerism can induce central and peripheral tolerance by deleting or regulating donor-reactive lymphocytes, while microchimerism may help sustain long-term graft acceptance but is not uniformly protective. Clinical trials combining kidney or liver transplants with donor stem cell infusions have shown that mixed or even transient chimerism can allow safe withdrawal of immunosuppression, though challenges include toxic conditioning, GVHD risk, inconsistent predictability, and unclear biomarkers. Advances in non-myeloablative regimens, regulatory cell therapies, costimulation blockade, precision immune monitoring, and bioengineering hold promise for making chimerism-based tolerance safer and more broadly applicable.