Bypass vein graft disease remains a significant limitation to the care of millions of patients with ischemic disease of the heart and lower extremities. The pathogenesis of this rapid, aggressive, occlusive disease lies in the remodeling response of the grafts themselves to the new arterial environment. As such, the molecular and cellular biology of neointimal hyperplasia provides a unique opportunity for cardiovascular researchers to more closely model a human clinical entity from its inception to the development of advanced disease. Recent years have therefore seen a broad new array of possible interventions for vein graft disease based on a sophisticated translation of genetic and molecular science. One of these applications, E2F decoys, has already progressed to phase III clinical studies, and many others will likely follow as the tools for therapeutic translation continue to improve. These include both gene transfer and gene blockade strategies.