Graft vascular disease (GVD) is the single most important long-term limitation to solid-organ transplantation. It is a concentric vascular intimal hyperplastic lesion composed of smooth muscle–like cells and associated matrix. GVD diffusely involves allograft vessels, eventually compromising perfusion and resulting in graft ischemia and failure. Animal models and an increasing sophistication in analyzing human GVD have provided important new insights into GVD pathogenesis. Innate and specific immune responses both participate in the initial vascular injury; GVD develops as a consequence of downstream chemokine- and cytokine-effector pathways. Other significant developments in the field include recognition of the central pathogenic role played by interferon-γ as well as the contribution of host cell precursors to the intimal lesions. Because GVD shares many features with more common vascular pathologies, insights gleaned from our understanding of allograft vasculopathy may well impact our treatment for “traditional” atherosclerosis or restenosis lesions.