Chronic rejection of allografts appears mechanistically distinct from acute antibody-mediated and or acute cell-mediated rejection. Histological features point to roles for alloantibody and lymphocytic infiltrates, and allograft vasculopathy is a common feature in chronic rejection of several different solid organs. Vasculopathy, in turn, can cause late graft failure due to chronic ischemia, parenchymal cell loss, and replacement fibrosis. Molecular analyses implicate graft vascular endothelial cells in this process. Here, we review evidence favoring a hypothesis linking alloantibody and complement to induction of endothelial cell surface expression and trans-presentation of IL-15 as a critical signal that enhances lymphocyte activation during antigen-mediated recruitment of alloreactive T cells. These T cells trans-migrate into the intima and secrete interferon-γ, which acts both on vascular smooth muscle cells within the arterial wall to stimulate their proliferation, resulting in vasculopathy, and back on the endothelial cells to provide positive feedback for this sequence of events.