GPCRs constitute the largest transmembrane protein family with more than 800 members. They serve as gatekeepers, controlling transduction for a variety of physiological and pathogenic signals, and are involved in almost every aspect of physiological activities in our human body. It is therefore easy to imagine that any GPCR signaling dysfunction probably leads to a disease such as cancer, cardiac failure, neurological disease, Parkinson’s, obesity, etc. Although only 10% of GPCRs have been subjected to drug discovery, they are already targeted by nearly 35% of FDA-approved medications, indicating a continued tremendous potential in drug discovery.