Salvinorin A (1) is a selective, potent kappa opioid receptor (KOR) agonist with unique structural and pharmacological properties. In mice, this non-nitrogenous ligand has been shown to produce analgesic properties against thermal nociception. Thus, it is believed that salvinorin A may be useful in the search for novel KOR therapeutics. In order to gain insight into how salvinorin A interacts at the KOR, a combination of site-directed mutagenesis and chimeric studies were conducted. Our studies suggest that salvinorin A binds at a unique epitope, utilizing residues along the transmembrane (TM) II /TM VII interface. Additionally, chimeric results indicate the importance of extracellular loop 2. A structural model of salvinorin A interacting at this novel epitope and the resulting implications will be presented.