When mice are lethally irradiated and reconstituted with allogeneic bone marrow cells, their skin is repopulated over a period of several months with Langerhans cells (LC) of marrow donor origin. Skin from such mice, when transplanted to unirradiated syngeneic recipients, became in many cases the sites of intense inflammatory responses that led to varying degrees of destruction of the transplanted skin and in some instances, to rejection of the entire graft. The frequency and intensity of these responses were influenced by the nature of the immunogenetic disparity between the donors and recipients of the marrow cells. Chimeric skin placed on hybrid mice derived from crosses between the marrow donors and recipients behaved in all respects as syngeneic grafts or autografts. When the recipients of the chimeric skin were presensitized to the antigens of the marrow donor, the responses were especially intense, and resulted in all cases in complete rejection. Thus the immunologically mediated attack on the allogeneic LCs was accompanied by widespread and nonspecific destruction of bystander cells. In all cases, the inflammation and tissue damage were confined sharply to the grafted skin, showing clearly that nonspecific or indirect tissue destruction is entirely consistent with highly selective destruction of grafted tissues. This finding removes a major objection to postulated mechanisms of rejection that involve indirect destruction of grafted tissues.