Retinoid-related orphan receptors ROR alpha, -beta, and -gamma are evolutionarily related transcription factors belonging to the steroid hormone receptor superfamily. Studies of ROR mutant mice revealed that these receptors are critical in the regulation of a number of physiological processes. ROR alpha plays a key role in the development of the cerebellum particularly in the regulation of Purkinje cell differentiation and proliferation of granule cell progenitors. ROR alpha has also been implicated in the maintenance of bone tissue and mice deficient in ROR alpha exhibit a greater susceptibility to atherosclerosis. ROR gamma is essential for lymph node organogenesis and plays a key role in the generation or survival of lymphoid tissue inducer (Lti) cells. ROR gamma is also critical in thymopoiesis where it controls differentiation and promotes the survival of thymocytes by positively regulating Bcl-X(L) expression. Several studies have indicated a regulatory role for RORs in circadian behavior. In several tissues, the expression of RORs oscillates during circadian rhythm while mice deficient in ROR beta exhibit an altered circadian rhythm. ROR alpha and ROR gamma have been implicated in the control of various immune responses. Mice deficient in ROR gamma exhibit a reduced susceptibility to allergen-induced airway inflammation while ROR alpha null mice show a prolonged inflammatory response to lipopolysaccharide. Recent analyses of the crystal structure and transcriptional activity of RORs revealed that cholesterol and specific cholesterol derivatives behave as agonists of ROR alpha while certain retinoids function as partial antagonists of ROR beta and ROR gamma. These studies indicate that ROR activity and, as a consequence physiological processes regulated by RORs, can be modulated by exogenous (ant)agonists. Therefore, the discovery of new (ant)agonists may lead to the development of novel therapeutic strategies for human disease in which RORs have been implicated.