Despite the exploration of a large number of disparate drugs in animal models and clinical trials, no pharmacological intervention, with the exception of aggressive lipid lowering therapy has reduced late vein graft failure in man. The importance of devising more effective strategies is exemplified by the considerable economic consequences of vein graft failure. Worldwide, there are currently more than 1,000,000 coronary artery bypass graft surgery (CABG) operations a year, the same number of patients undergoing infrainguinal bypass (IIBS) for vascular diseases of the lower limb. The pathophysiology of vein graft failure is complex, involving disparate factors that include adhesion of platelets and leukocytes, rheological forces, metalloproteinase expression, proliferation and migration of vascular smooth muscle cells, neointima formation, oxidative stress, hypoxia and neural re-organisation. Although this diverse aetiology may seem to preclude any single drug type as being effective in preventing vein graft failure, one factor that is involved in every facet of vein graft pathobiology is endothelin-1 (ET-1). Thus, in this review, we will consider the diverse aetiology of vein graft disease in relation to ET-1 and will then present an argument (with evidence) that ET-1A (ETA) receptor antagonists constitute a potentially effective means of preventing vein graft failure.