Cholesterol homeostasis is maintained by a regulatory network that controls both the acquisition and elimination of cholesterol. Recent studies have elucidated a mechanism by which cholesterol metabolism is transcriptionally regulated by several classes of orphan nuclear receptors. In particular, the liver X receptors, LXRalpha and LXRbeta, appear to serve as key sensors of intracellular sterol levels by regulating the expression of genes that control cholesterol absorption, storage, transport, and elimination. LXRs are also involved in fatty acid metabolism by their ability to increase the expression of sterol regulatory element-binding protein 1c (SREBP-1c). These findings define LXRs as potential therapeutic targets for the treatment of lipid disorders.