The retinoic-acid-receptor-related orphan receptors (RORs) are members of the nuclear receptor (NR) superfamily whose activity has been implicated in several physiological and pathological processes. The RORs, specifically RORα and RORγ, are considered to be master regulators of T(H)17 cells, a recently described subset of CD4(+) T helper cells that have been demonstrated to have a pathological role in autoimmune disease. As with most members of the NR superfamily, RORs are ligand-regulated, suggesting that their activity can be modulated by synthetic ligands. Recent advances in the field have established that selective inhibition of the RORs is a viable therapeutic approach for not only the treatment of autoimmune disorders but also ROR-mediated metabolic disorders.