Although angioplasty has undergone considerable development, restenosis remains an unsolved problem. No drugs have been proved effective in the prevention of restenosis. Prophylactic stenting is the only treatment with some efficacy. The pathophysiology of restenosis involves both intimal hyperplasia with a major proliferative component at the dilated site and geometric constrictive remodeling of the artery. Stenting seems to prevent the remodeling but does not prevent and may even worsen the intimal hyperplasia. Gene therapy may be effective in preventing the proliferative component of the intimal hyperplasia: therapeutic genes can be delivered locally to the arterial wall cells at the dilated site during or immediately after angioplasty, using viral (e.g., adenoviruses) or nonviral vectors. The main candidate genes stimulate a variety of endogenous mechanisms whose effects consist in inhibition of smooth muscle cell proliferation (Rb gene); sensitization of proliferating cells to the effects of cytotoxic substances, thus allowing selective chemotherapy (HSV-tk gene); or stimulation of reendothelization (VEGF gene). Other genes have also yielded promising results (ecNOs, p21, Coxl, etc.). Clinical application of these techniques cannot be envisioned until studies are available proving that the delivery methods (transfer vectors or local delivery systems) are completely safe, and that the candidate genes are effective in "realistic" models. If these hurdles are cleared successfully, preventive gene therapy for gene restenosis may well become a clinical reality.