Normal syngeneic recipients rejected a substantial proportion of skin grafts following their retransplantation after a period of residence on tolerant allogeneic or normal semi-allogeneic hosts. Rejection was often atypical in its delayed onset and protracted course. Examination of the effect of a variety of manipulations of graft donors and of intermediate hosts revealed that active involvement of cells derived from both categories was required for the initiation of an allograft reaction after transfer to the ultimate, syngeneic recipient. Liability of retransplanted syngeneic skin grafts to rejection could be almost entirely abolished by their exposure to 300 rads irradiation before placement on the intermediate host. Skin from neonatally thymectomized donors or from rats specifically tolerant of the intermediate F1 hybrid host was much less liable to ultimate rejection than was skin from normal hosts. These experiments suggest that rejection of re-transplanted, syngeneic grafts may result from some form of activation of cells of the graft during its period on the intermediate host.