This podcast episode explores orphan nuclear receptors, focusing on Rev-Erb and ROR, which are important for circadian rhythms and metabolism. The discussion covers how scientists are working to discover their activating ligands through methods like large-scale screening and computational modeling. The episode delves into the challenges and potential therapeutic applications, particularly for sleep disorders, metabolic diseases, and cancer. It also examines how studying well-understood receptors like the thyroid hormone receptor can provide insights into these mysterious orphan receptors.