A primary pathologic response to vascular injury is the proliferation and migration of vascular smooth muscle cells and the development of neointimal lesions. An increasing body of knowledge regarding the molecular and genetic basis of neointimal disease has created a unique opportunity for the treatment of this complex disorder. Gene therapy attempts to correct pathobiological processes by either inhibiting or correcting cellular functions at the level of gene expression. These endpoints are achieved by the delivery of either functional genes or oligonucleotides, capable of interfering with a cell's programmed machinery. Since the early 1990s, the evolution of this technology, along with an ever-expanding source of pathobiological information, has led to many novel approaches for the treatment of restenosis in arterial balloon injury as well as vein graft bypass failure. Using a variety of targets, inhibition of proliferation has predominantly been achieved through direct disruption of the cell cycle machinery. In addition, others have demonstrated successful inhibition by interfering with the signals for cellular proliferation or the enhancement of anti-proliferative stimuli. As this exciting therapeutic alternative evolves, improvements in safety, specificity and efficiency will enhance the likelihood of widespread clinical application.