The orexin/hypocretin peptides orexin A and orexin B (also known as hcrt-1 and hcrt-2) are 33- and 28-amino acid peptides, respectively, that are preferentially expressed in hypothalamus. The orexins bind to two GPCRs, OX1 and OX2, to increase intracellular calcium. Orexins function to increase wakefulness, primarily through OX2, which has been shown to harbor the causative mutation in narcoleptic dogs (Lin et al., 1999). In addition, the orexinergic system plays a role in feeding and stress responses (Kukkonen et al., 2002). The cloned human OX2-expressing cell line is made in the Chem-1 host, which supports high levels of recombinant OX2 expression on the cell surface and contains high levels of the promiscuous G protein Gα15 to couple the receptor to the calcium signaling pathway. Thus, the cell line is an ideal tool for screening for antagonists of interactions between the OX2 and its ligands.