Vascular bypass surgery involves the use of a vascular conduit to circumvent a site of vascular compromise. Vascular graft failure continues to plague both the patients receiving and the surgeons performing these interventions. Demand for the development of a therapy to reduce intimal hyperplasia--the most common cause of bypass graft failure--is significant and has been the goal of many biotechnology groups. The development of gene therapy as a feasible clinical intervention has allowed for novel methods of inhibiting intimal hyperplasia to be conceived. This review describes the evolution of gene transfer of the inducible nitric oxide synthase (iNOS) gene, one of the most successful preclinical interventions to date for vascular disease.