The NR4A subfamily of nuclear orphan receptors comprises three members Nur77, Nurr1 and NOR-1 that are each expressed in the vessel wall in response to injury and in atherosclerotic lesion macrophages. To study the function of NR4As in vascular smooth muscle cells, endothelial cells and monocyte/macrophages gain of function and siRNA-mediated knock-down experiments have been performed in cultured cells and in dedicated mouse models. Nur77 has been shown to inhibit the formation of smooth muscle cell-rich lesions, to promote endothelial cell survival and to modulate the inflammatory response of macrophages. Most recently, small-molecule activators of NR4As such as 6-mercaptopurine have been identified to modulate the transcriptional activity of these nuclear receptors in experimental model systems. In this chapter we will present the knowledge currently available on vascular actions of NR4As and the function of these nuclear receptors in metabolism will be reviewed briefly. A clinical perspective to approach NR4As as targets for intervention in vascular disease will be given as well as directions for future research.