Based on phylogenetic analysis, the family of cannabinoid receptors is separated into two different classes of the rhodopsin-like family of GPCRs. While CB1 and CB2 receptors share a group together with lysophospholipid (LPL) and melanocortin receptors (GPCR-A13), the newly recognized GPR55, GPR119, and GPR18 receptors are officially member of another group (GPCR-A15), together with protein activated receptors (PAR) and other LPL receptors. Two orphan GPCRs have recently been implicated as novel cannabinoid receptors; these are GPR119, which has been proposed as a receptor for oleoylethanolamide, and GPR55 which has been proposed as a receptor activated by multiple different cannabinoid ligands. GPR55 has been demonstrated to interact with chemically unrelated cannabinoid ligands, in both mammalian and non-mammalian recombinant expression systems, and by independent research groups. Clearly, there is some relationship between the ligand-binding sites of GPR55 and CB1/CB2; however, the endogenous agonist and physiological relevance of GPR55 are not yet clear. Studies have suggested that L-α-lysophosphatidylinositol (LPI), which activates GPR55 but not CB1 or CB2 receptors, could be its endogenous ligand. Conversely, cannabidiol (CBD, Axon 1234) is a GPR55 antagonist. GPR119 is strongly implicated in the regulation of energy balance and body weight. However, further corroborating data of the activity of acylethanolamides at GPR119 will be required before it can be regarded unequivocally as a cannabinoid receptor.