Abstract PROJECT SUMMARY G protein coupled receptors (GPCRs) represent essential molecular targets for a large number of approved as well as investigational medications. Of the 380 or so non-olfactory GPCRs in the human genome around 100 are understudied and/or orphan receptors (oGPCRs). The oGPCRs represent potential therapeutic targets although discovering drugs that modulate them is challenging. Here we will solve the structures of 15-20 oGPCRs using cryogenic electron microscopy (cryo-EM). The solved structures then will serve as templates for structure-guided drug discovery targeting these oGPCRs.