Most GPCR form protein families composed of functionally and/or structurally related subtypes. The subtype-selective ligands are highly desired for both pharmacological tools and drug discovery. However, high protein sequence homologies within a receptor family hamper developing subtype-selective ligand. Our purpose is to develop new methods for selective activation of target receptor subtype using chemogenetic approach in which the target receptor is genetically engineered to interact with a designed chemical partner selectively. In this direction, we have recently developed chemogenetic methods for activating mGlu1, a metabotropic glutamate receptor subtype. This approach allowed chemogenetic regulation of mGlu1 endogenously expressed in mice. Although powerful, it may be hard to apply this method in vivo due to the unclear pharmacokinetics of the designed ligands. In this context, we are now developing new chemogenetic methods for in vivo application. In this symposium, I will present the recent progress of our GPCR chemogenetics and discuss perspectives toward covalent drugs using our chemogenetics.