Atherosclerosis is the underlying pathology of many cardiovascular diseases. The formation and rupture of atherosclerotic plaques in the coronary arteries results in angina and myocardial infarction. Venous coronary artery bypass grafts are designed to reduce the consequences of atherosclerosis in the coronary arteries by diverting blood flow around the atherosclerotic plaques. However, vein grafts suffer a high failure rate due to intimal thickening that occurs as a result of vascular cell injury and activation and can act as 'a soil' for subsequent atherosclerotic plaque formation. A clinically-proven method for the reduction of vein graft intimal thickening and subsequent major adverse clinical events is currently not available. Consequently, a greater understanding of the underlying mechanisms of intimal thickening may be beneficial for the design of future therapies for vein graft failure. Vein grafting induces inflammation and endothelial cell damage and dysfunction, that promotes vascular smooth muscle cell (VSMC) migration, and proliferation. Injury to the wall of the vein as a result of grafting leads to the production of chemoattractants, remodelling of the extracellular matrix and cell-cell contacts; which all contribute to the induction of VSMC migration and proliferation. This review focuses on the role of altered behaviour of VSMCs in the vein graft and some of the factors which critically lead to intimal thickening that pre-disposes the vein graft to further atherosclerosis and re-occurrence of symptoms in the patient.