Current therapies for the treatment of atherosclerotic vascular disease are aimed at either disrupting or bypassing flow-limiting lesions. Preventative strategies are necessary to decrease the burden of disease but are limited by genetic predispositions to certain diseases and the body's innate response to injury. Gene therapy, defined as the purposeful therapeutic overexpression or attenuation of a gene product, has enormous potential benefits in vascular disease prevention and treatment strategies. This article reviews the scientific considerations involved in the development of gene therapy strategies and outlines some of the gene products that are currently being used. These interventional genetic approaches will be reviewed in the context of specific vascular disease processes, including atherosclerosis, restenosis, and thrombosis. Gene therapy will serve an enhancing and adjuvant role to evolving surgical therapies.