Patency rates for coronary artery bypass grafting (CABG) procedures using autologous saphenous vein (SV) remain poor. The vast majority of failures are due to neointima formation and superimposed atherosclerosis. There remains a requirement to develop a novel therapy through which to improve patency rates. Since many of the molecular and cellular mechanisms that lead to neointima formation have been identified, a number of strategies have emerged. These include modulation of smooth muscle cell migration, proliferation and/or apoptosis, acceleration of endothelial regeneration and improvement in endothelial function. Vein grafting is highly suited for human gene therapy since it allows ex vivo manipulation of the vein prior to grafting into the coronary circulation of the patient. This has clear safety advantages over in vivo gene therapeutic applications but, due to the short clinical window through which gene transfer can be administered, efficient vector systems are required. Adenoviral vectors have proven efficient for gene delivery in this context although expression of transgenes using first-generation vectors is transient in nature and associated with inflammation. However, this may be advantageous since a number of candidate therapeutic transgenes have been targeted to either block vascular smooth muscle cell migration and/or proliferation or to promote apoptosis. Our research has shown that overexpression of certain genes, including TIMP-3, p53 and NogoB has a beneficial effect by reducing neointima formation. This represents a valid therapeutic strategy to prevent vein graft failure in patients. In addition, we have developed a number of engineering strategies to manipulate the tropism of the adenovirus capsid to enhance gene delivery to the smooth muscle cell compartment.