Besides the increasing number of categorized GPCRs with assigned endogenous ligands and (partially) elucidated signaling pathways, a large number of GPCRs remain whose endogenous ligands are unknown, and are classified as orphan GPCRs. Traditionally this class of GPCRs has been difficult to study and although molecular biological and bioinformatics techniques made the identification of orphan GPCRs amenable, the development of therapeutic compounds targeting these receptors has been extremely slow. Nevertheless, these GPCRs are considered important targets based on their distribution and behavioral phenotype as revealed by animals lacking the receptor[1] and [2].