Medawar and co-workers originally demonstrated that injection of donor bone marrow (DBM) into immuno-incompetent neonatal rodents could induce tolerance to grafts from animals of the same strain as the bone marrow donor'. Induction of tolerance in this manner can also be accomplished in mature mice, dogs and monkeys if the resident T-cell populations in the recipient are depleted by a polyclonal antithymocyte globulin or an anti-T cell immunotoxin. The molecular mechanisms by which bone marrow cells mediate the induction of tolerance remain uncertain. Here we examined a well- established adult mouse model of antithymocyte globulin and DBM treatment and show that expression of functional Fas ligand (FasL, also CD95L) on the injected bone marrow cells is required for tolerance induction. The results indicate that a state of microchimerism per se is insufficient for the induction of tolerance in T cell-depleted transplant recipients. Moreover, the results are consistent with the hypothesis that tolerance induced by DBM involves an apoptotic process leading to deletion of graft-reactive cells.