A greater understanding of the molecular and genetic bases of cardiovascular diseases has made the design of therapeutic genetic interventions feasible in these clinical entities. Bypass vein graft failure represents a serious limitation in the long-term treatment of occlusive disease in the coronary and peripheral circulations, and traditional pharmacotherapeutic approaches have not significantly affected the course of vein graft disease. Direct access to vein graft tissue at the time of operation may provide a practical means of manipulating graft function at the genetic level, and an intraoperative genetic engineering strategy has, in fact, been developed that inhibits the neointimal hyperplasia and accelerated atherosclerosis that are at the root of most graft failures. The molecular basis for this approach is explored, as is the potential for other genetic vein graft manipulations.