Although considerable progress has been made in the prevention and treatment of atherosclerotic cardiovascular disease, new therapeutic strategies are still needed. Atherosclerosis is a systemic disease and represents an attractive target for the development of somatic gene transfer intended to modulate systemic factors with the goal of inhibiting disease progression. This approach should be differentiated from localized vascular gene delivery to isolated atherosclerotic lesions such as that intended to prevent restenosis. Systemic gene therapy for atherosclerosis can involve either: 1) gene replacement therapy in patients with defined genetic disorder causing premature atherosclerosis, or 2) overexpression of proteins which directly or indirectly inhibit atherosclerosis or stabilize vulnerable lesions. The former is conceptually straightforward, and a pilot clinical gene therapy trial for one of these diseases, homozygous familial hypercholesterolemia, has already been reported. The latter has significant potential for eventual application to a large number of patients at risk for progressive atherosclerosis, independent of the specific cause. However, substantial progress in vector development and the demonstration of efficacy in relevant animal models will be required before gene therapy for atherosclerosis becomes a clinical reality.