CHRONIC rejection (CR) primarily manifests itself as a progressive obliterative arteriopathy (OA) that most frequently affects medium-sized muscular arteries of vascularized organ allografts. The lack of similar changes in isografts argues strongly for an immunologic basis. The most widely accepted hypothesis proposed to explain CR suggests that direct immunologic injury to the graft endothelium mediated by alloreactive cells and/Or antibodies triggers a vascular wall repair response driven by cytokines and growth factors. It will be referred to here as the "direct injury" modeL This response can be made worse by hyperlipidemia or ameliorated by drugs that block the immunologic insult or the vessel wall response. Despite successful application of this line of reasoning. several morphologic observations on failed allografts with CR are not readily explained by the direct injury model, as illustrated by the following examples: (1) OA preferentially involves medium-sized muscular arteries with accentuation of the changes near first and second order branch points; (2) OA changes are less severe in smaller arteries and veins. despite an antigenically similar endothelium: (3) OA is not a complication of graft-versus-host disease. despite being an immunologic mirror image of rejection: (4) OA is not always preceded by intimal inflammation or endothelial disruption detectable by light microscopy; (5) mechanical factors in medium-sized arteries are not conducive to lymphocyte attachment and exocytosis, except during severe immunologic reactions; (6) the reasons for an antigendependent and antigen-independent phases of OA are not readily apparent. Many of these peculiarities suggest that mechanical factors also contribute to the development of OA. Moreover. the direct injury model does not address the immunopathogenic mechanisms responsible for the persistent immunologic injury. An effort has been made in recent years by our group to reconcile these inconsistencies in clinical tissue samples and a small animal model of CR, which was inadvertently uncovered while conducting experiments on the significance of microchimerism.1.2 In that model, Brown-Norway (BN) rats are pretreated with a Lewis (LEW) bone marrow (BM) infusion or an orthotopic liver allograft (OL T) and a short. 2-week course of immunosuppression with Tacrolimus:' These pretreated recipients arc then challenged 100 davs later with a heterotopic LEW heart allograft without im· munosuppression.