At homeostasis, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in the arterial wall are fully differentiated and display a very low proliferative index. However, unlike terminally differentiated cells, mature ECs and VSMCs maintain their ability to dedifferentiate and reenter the cell cycle in response to several environmental stimuli. Because of the contribution of EC and VSMC proliferation to the pathogenesis of several diseases, including cancer and cardiovascular disease, considerable effort has been devoted to elucidate the mechanisms that regulate cell cycle progression in these cell types. These regulatory networks and the implications they may have for cardiovascular disease are reviewed here.