Retinoid-related orphan receptors alpha (RORα) and gamma (RORγ) are both expressed in liver; however, their physiological functions in this tissue have not yet been clearly defined. The RORα1 and RORγ1 isoforms, but not RORα4, show an oscillatory pattern of expression during circadian rhythm. To obtain insight into the physiological functions of ROR receptors in liver, we analyzed the gene expression profiles of livers from WT, RORα-deficient staggerer (sg) mice (RORαsg/sg), RORγ-/-, and RORαsg/sgRORγ-/- double knockout (DKO) mice by microarray analysis. DKO mice were generated to study functional redundancy between RORα and RORγ. These analyses demonstrated that RORα and RORγ affect the expression of a number of genes. RORα and RORγ are particularly important in the regulation of genes encoding several phase I and phase II metabolic enzymes, including several 3β-hydroxysteroid dehydrogenases, cytochrome P450 enzymes, and sulfotransferases. In addition, our results indicate that RORα and RORγ each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that RORα and RORγ receptors influence the regulation of several metabolic pathways, including those involved in the metabolism of steroids, bile acids, and xenobiotics, suggesting that RORs are important in the control of metabolic homeostasis. Copyright © 2005 by the American Physiological Society.