Saphenous vein graft failure remains a significant clinical and economic burden. Although increased use of arterial conduits has improved long-term outcome, the majority of bypass procedures continue to use saphenous vein. Early vein graft patency is maximized by avoiding damage at the time of implantation, meticulous surgical technique, and appropriate use of antithrombotic therapy. No surgical technique or pharmacological intervention, however, has been shown to prevent late occlusion, which results from the progression of intimal vascular smooth muscle cell proliferation and superimposed atheromatous changes. Over the last few years, there has been a dramatic increase in our understanding of the biology of the vessel wall and the cellular and humoral influences on the process of intimal vascular smooth muscle cell proliferation. This has been possible principally through the advancement and application of molecular biological techniques. Although pharmacological therapies to prevent intimal hyperplasia continue to be evaluated, it is again the new series of strategies made possible by molecular biology that provide the most exciting prospects for treatment. Development of specific antibodies, antisense oligonucleotides, and vascular gene transfer represent potentially effective therapies, not only for the prevention of vein graft failure but also for a whole range of cardiovascular diseases.