Uncoupling protein 2 (UCP-2) is a newly identified member of the mitochondrial anion carrier family and shares 60% sequence identity with the well-characterized thermogenic UCP-1 from brown adipose tissue. Several lines of evidence suggest that UCP-2 is involved in the control of reactive oxygen species (ROS) production by mitochondria. More recently, a direct role for UCP-2 in the regulation of atherogenesis has been suggested by the observation that bone marrow transplantation from UCP-2-deficient mice to low-density lipoprotein receptor-deficient mice markedly increased atherosclerotic lesion size. This review introduces the possible role of UCP-2 in the regulation of atherogenesis in vascular cells. Although the relative contribution of the individual ROS generating systems in the vasculature is still ambiguous, both cell membrane NAD(P)H oxidase and the mitochondrial electron-transport chain have been proposed to play significant roles in the overproduction of ROS. UCP-2 can possibly modify atherosclerotic processes initiated in vascular cells and agents that increase UCP-2 expression in vascular cells may help prevent the development and progression of atherosclerosis in patients with diabetes or hypertension.