Abstract Neointimal hyperplasia in aortocoronary vein grafts represents a significant problem that, by itself or by development of vein graft atherosclerosis, leads to the return of symptoms and to major adverse cardiac events after coronary artery bypass grafting. The main causes of neointimal hyperplasia are surgical trauma, intraoperative ischemia reperfusion injury, and implantation of a vein into the arterial circulation. All these pathogenetic factors cause a loss of protective endothelial mediators. The initiating steps lead to the induction of a significant inflammatory response and to the production of mitogenic factors in the vascular wall. DNA synthesis in vascular smooth muscle cells is markedly up-regulated, and intracellular signal transduction leads to transcription of immediate early genes, which causes an intense proliferative response. Vascular smooth muscle cells proliferate, migrate through the internal elastic lamina with the support of proteases, and transform from contractile-type into secretory-type cells. A thick layer of neointima is formed. The prevention of neointimal hyperplasia includes meticulous surgical technique, the choice of a large target vessel, and adequate intraoperative storage of the vein graft. Local intraoperative therapy of the implanted graft has been successfully tested in the experimental setting with a variety of substances that tackle different steps in the pathologic mechanism. Systemic pharmacologic therapy in clinical use primarily consists of the use of platelet inhibitors and anticoagulants. The transfer of experimental knowledge to bedside application has been slow. Gene therapy represents a promising field for the improved management of vein graft neointimal hyperplasia.