Although G protein-coupled receptors (GPCRs) are successful therapeutic targets for 35% of FDA-approved medications, roughly 120 remain orphan receptors with poorly understood physiology and pharmacology.  This session will bring together experts working on the structure, signaling, physiology and novel pharmacology of orphan GPCRs. Speakers will discuss their recent research on orphan receptors expressed in the nervous system including GPR158, GPR151, GPR52 and MRGPRX4. Research will include descriptions of high-resolution orphan receptor structures, unexpected receptor signaling mechanisms, novel agonist/antagonist modes-of-action, neurophysiology and drug discovery. These studies are providing new pharmacological tools to better define the function of these understudied GPCRs, and opening new directions for both basic and translational pharmacology.