Atherosclerosis is the primary cause for the global burden of disease accounting for the number one and two causes of death and disability in the world, namely, coronary artery disease and strokes. Multiple processes such as endothelial dysfunction, inflammation, vascular proliferation, and modulation of matrix are linked to the development of atherosclerosis. Vascular smooth muscle cell (VSMC) proliferation is the key etiological factor in primary atherosclerosis and in the pathophysiology of post-intervention restenosis, transplant vasculapothy, and vein bypass graft failure. VSMC proliferation is linked to other cellular processes such as inflammation, apoptosis and matrix modification that contribute to atherosclerosis. Consequently, suitable therapeutic approach is to inhibit or block the pathological processes of VSMC proliferation by targeting cell cycle regulation. Pathogenesis of atherosclerosis is very complex and involves interplay of both genetic and environmental factors. The major risk factors for atherosclerosis are hypertension, hyperlipidemia, diabetes, obesity, smoking, xenobiotics, and viral and bacterial infection. Controlling these risk factors is as critical as is an understanding of atherosclerosis pathogenesis. Clinical advances for the treatment of many of these major risk factors have been huge and effective in the past two decades such as for the hypertension, hyperlipidemia, diabetes, and smoking. However, antiproliferative therapeutic strategies targeting the cell cycle regulation are still in their infancy. In this article, the current understanding of the pathogenesis of atherosclerosis will be reviewed along with the clinical advances in the treatment of vascular proliferative diseases and the status of molecular and gene therapeutic approaches in disease prevention.