Nuclear receptors form a large family of ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. Several of these receptors have been demonstrated to play important roles in controlling biological processes that influence the development and clinical consequences of atherosclerosis. Because nuclear receptors are regulated by small molecules, they are potential targets for anti-atherogenic drugs. In this chapter, we review the use of mouse models to evaluate roles of nuclear receptors and their ligands in the pathogenesis and treatment of atherosclerosis.