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Despite advances in the medical management of atherosclerosis, surgical revascularization using autologous veins remains a mainstay of therapy for both coronary and peripheral artery disease. However, long-term outcomes following bypass surgery are limited by relatively high failure rates due to vein graft disease. Vein graft failure, together with the limited supply of native veins, has led to interest in gene therapy to prevent vein graft disease. Bypass grafting presents an ideal opportunity for gene therapy because vein grafts can be treated with gene delivery vectors ex vivo to maximize gene delivery, minimize systemic toxicity, and target the pathogenesis of vein graft disease at its onset. Here we discuss the pathogenesis of vein graft disease, vector delivery strategies, and potential molecular targets for preventing vein graft disease. We summarize the preclinical and clinical literature on gene therapy in vein grafting and discuss considerations for future therapies to prevent vein graft disease.