Saphenous vein (SV) is an excellent conduit for revascularization, especially for patients with multi-vessel coronary artery disease and peripheral arterial disease. However, its patency is limited in comparison with arterial grafts. Vein graft occlusion is the result of intimal hyperplasia and accelerated development of atherosclerosis, a cellular response triggered by surgical trauma, hypoxia, and increased wall stress. Nevertheless, the cellular mechanisms of vascular disease following bypass graft implantation, especially the impact of vein preparation and surgical techniques are less known than those that occur after angioplasty. The present article reviews the molecular mechanisms of vein graft remodeling, specifically thrombosis, alteration in endothelial function, modification of signaling pathways leading to cell proliferation and migration, role of intracellular calcium and activation of matrix metalloproteinases. The procedures of vein harvesting are discussed from the point of view of its possible impact on graft remodeling. Special attention is devoted to the consequences of pressure distention of the vein during the preparation for grafting; and an alternative preparation, which allows overcoming vasospasm without distention is discussed. The effects of pharmacological treatment during the preparation procedure and during arterialization are also discussed. An external support of the graft has been suggested to reduce graft remodeling, and its effects on the vascular mechanisms during arterialization are also considered. In conclusion, adjustment of the vein harvesting and preparation procedures combined with pharmacological treatment targeting the vasoconstrictor and proliferative mechanisms could improve long term vein graft patency.