Chronic rejection is widely regarded as difficult to diagnose, of obscure etiology, untreatable, and irreversible. The immunological basis of transplant arteriopathy (TA) is under active investigation. The belief that the process is immunologically mediated is based on the observations that TA rarely arises in auto grafts. Three separate and possibly synergistic pathways have been identified: T-cells, antibody-mediated injury, and natural killer (NK) cells. The majority of late kidney graft losses are associated with donor-specific antibodies (DSA) and/or C4d deposition, and the risk of subsequent graft failure is significantly worse after a C4d+ biopsy. Transient lobular hepatitis may also be a feature of chronic rejection and is potentially reversible, although vanishing bile duct syndrome (VBDS) and TA are resistant to current therapy. The lesions of chronic rejection in the lung consist of TA and a lesion occluding airways that is termed obliterative bronchiolitis (OB).