Atherosclerosis is a major health problem in the western world, and the effectiveness of interventional therapeutic modalities for symptomatic atherosclerotic lesions is limited by vessel restenosis. Proliferation and migration of smooth muscle cells (SMCs) play a central role in post-interventional restenosis. Accordingly, many therapeutic approaches attempt to inhibit SMC proliferation. As the cell cycle is a final common pathway in SMC proliferation, proteins of the cell cycle have emerged as logical targets for the treatment and prevention of restenotic lesions. In this review we discuss current approaches that target the cell cycle in smooth muscle cells, and also describe recent and ongoing clinical trials that involve cell-cycle manipulation in the treatment of vasculoproliferative diseases.