Atherosclerosis is a degenerative process characterized by endothelial cell dysfunction, inflammatory cell adhesion and infiltration, and the accumulation of cellular and matrix elements leading to the formation of fibrocellular plaques. In the end stages, advanced occlusive plaques limit blood flow and oxygen delivery resulting in the well-known ischemic syndromes of the coronary, skeletal muscle, mesenteric, and cerebrovascular circulation. Moreover, sudden critical ischemic events may be precipitated by plaque disturbance, rupture, hemorrhage, and/or thrombosis. Traditional pharmacologic approaches have been effective in reducing serum cholesterol and controlling thrombosis but, in the main, have had little impact on the treatment of advanced lesions. The purpose of this review is to examine the current status of gene therapy for vascular proliferation, aberrant endothelial function, thrombosis, peripheral ischemia, and modification of the blood/biomaterial interface.