G-protein coupled receptors (GPCRs) play a key role in a broad range of biological processes by binding to a wide variety of signaling molecules, which have resulted in 34% of all FDA-approved drugs which target GPCRs. The human genome encodes for approximately 800 GPCR members of which about 140 non-olfactory receptors remain orphans with an unknown function and endogenous ligand. Despite prolonged efforts to deorphanize the unresolved receptors, they remain orphans until this day. By studying scientific publications, this thesis has clarified the challenges with the deorphanization of GPCRs to explain why there are still so many orphan GPCRs when they have confirmed involvement in so many human disorders.