Aortocoronary saphenous vein bypass grafting relieves anginal pain in patients with coronary artery disease. However, its effectiveness is limited due to graft failure; the 10-year patency rate is 50%-60%. Early, 1-year and late graft failure may be due to thrombosis, fibrointimal hyperplasia and atherosclerosis, respectively. There is general agreement that vein graft atherosclerosis differs from arterial lesions in terms of temporal and histological changes. Vein graft atherosclerosis is more rapid, with diffuse concentric changes and a less noticeable fibrous cap, making venous plaques more vulnerable to rupture and subsequent thrombus formation. Despite progress in understanding the pathophysiology, some aspects of vein graft atherosclerosis need to be clarified. This review focuses on the pathophysiologic aspects of this widespread, costly and disabling disease, with emphasis on late graft occlusion and distinctions between arterial and venous atherosclerosis in terms of histology, pathophysiology and risk factors.