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Ligands for about half of the nuclear receptor superfamily, many members of which are involved in crucial metabolic pathways, have been identified so far. Those receptors, for which the ligands are not known, are called orphan nuclear receptors. Finding the ligands for these receptors is a big challenge for pharmaceutical companies. In his Perspective, Gustafsson discusses the new discovery (as reported by Parks et al. and Makishima et al. in this issue) that the ligands for the farnesoid X receptor, FXR, are bile acids, important regulators of cholesterol homeostasis. Intriguingly, when bound to FXR, bile acids are able to regulate their own synthesis from cholesterol by suppressing production of a crucial biosynthetic enzyme.