Revascularization with vein grafts is standard surgical therapy for occlusive arterial diseases. Autologous saphenous vein grafts are important conduits for repairing blocked coronary arteries and are used in the majority of vein graft procedures. Up to 50% of saphenous vein grafts will be occluded during the first decade after surgery. Vein graft occlusion occurs as a result of neointimal hyperplasia, which takes place in response to hemodynamic changes and vessel wall injury, and is characterized by the migration and proliferation of vascular smooth muscle cells. Intimal hyperplasia is further complicated by the concomitant development of atherosclerosis and thrombosis. In the absence of effective pharmacological interventions for the treatment and prevention of occlusive vein graft disease, gene therapy has emerged as a potential therapeutic alternative. Gene therapy could improve vein graft patency by reducing early thrombosis, neointimal hyperplasia and atherosclerosis. In this review we will summarize the emerging applications of gene therapy as a therapeutic tool in occlusive vein graft disease.