Gene therapy holds great promise for treating both genetic and acquired disorders. However, progress toward effective human gene therapy has been thwarted by a number of problems including vector toxicity, poor targeting of diseased tissues, and host immune and inflammatory activity to name but a few of the challenges. Gene therapy for cardiovascular disease has been the subject of many fewer clinical trials than other disorders such as cancer or cystic fibrosis. Nevertheless, the challenges are comparable. The present paper reports a review of investigations related to our hypothesis that site specific cardiovascular gene therapy represents an approach that can lead to both optimizing efficacy and reducing the impact of gene vector-related systemic adverse effects. We report experimental studies demonstrating proof of principle in three areas: gene therapy for heart valve disease, gene delivery stents, and gene therapy to treat cardiac arrhythmias. Heart valve disease is the second most common indication for open heart surgery and is now only treatable by surgical removal or repair of the diseased heart valve. Our investigations demonstrate that gene vectors can be immobilized on the surface of prosthetic heart valve leaflets thereby enabling a therapeutic genetic modification of host cells around the valve annulus and on the leaflet. Other animal studies have shown that vascular stents used to relieve arterial obstruction can also be used as gene delivery systems to provide therapeutic vector constructs that can both locally prevent post stenting reobstruction, known as in-stent restenosis, and treat the underlying vascular disease. Cardiac arrhythmias are the cause of sudden death due to heart disease and affect millions of others on a chronic basis. Our group has successfully investigated in animal studies localized gene therapy using an ion channel mutation to treat atrial arrhythmias.