The orphan G protein coupled receptor, GPR55, has gained notoriety because of its putative identification as a cannabinoid receptor subtype. The significance of this assignment should not be underestimated given the importance of cannabinoids to drug abuse and the potential utility of cannabinoid ligands in treating behavioral disorders leading to conditions such as obesity. The validity of assigning GPR55 to the cannabinoid family is problematic based upon the discovery that endogenous compounds not related to cannabinoid receptor ligands also bind and signal through GPR55. As a consequence, it is important to identify GPR55-selective ligands that can precisely define GPR55’s role in regulating addictive behaviors. Lysophosphatidylinositol (LPI; 1.2 μM) is representative of the recently identified endogenous GPR55 ligands and the CB1 inverse agonist/antagonists SR141716A (3.9 μM) and AM251 (9.6 μM), that are also GPR55 agonists, are representative of the cannabinoid receptor ligands that were screened against GPR55 when selectivity was not a consideration. The availability of high potency selective GPR55 agonists will therefore facilitate the study of this receptor’s signaling. We have identified 3 potent and selective agonists for GPR55, which represent 3 different chemical scaffolds: 1) a morpholinosulfonylphenylamide, ML186 (CID15945391) with 305 nM potency for GPR55 and >100-fold selectivity against GPR35, CB1 and CB2 (as agonist and antagonists); 2) a tricyclic triazoloquinoline, ML185 (CID1374043) with 658 nM potency for GPR55 and >48-fold selectivity against GPR35, CB1 and CB2 (as agonists and antagonists); and 3) a piperazine, ML184 (2440433) with 263 nM potency for GPR55 and >120-fold, 83-fold, and 57-fold selectivity against GPR35, CB1 and CB2 as antagonists, and >120-fold selective against all 3 counter receptors as agonists. All three probes also are active in activating the downstream responses of ERK phosphorylation and PKC β II translocation.