Atherosclerosis is the leading cause of mortality in the Western world, and new therapeutics to target the metabolic and inflammatory factors that underlie its pathogenesis are needed. Peroxisome proliferator-activated receptors and liver X receptors are lipid-activated nuclear receptors that regulate systemic glucose and lipid metabolism, and modulate inflammation within the vascular wall. New understanding of their functions in physiology and the development of high-affinity synthetic ligands highlight their potential as targets for the treatment of cardiovascular disease.