GPCRs have proven to be a valuable target family for drug discovery with more than 30% of marketed drugs acting through this receptor superfamily. However, numerous members remain challenging with no selective and druggable ligands being successfully developed. For these difficult targets, novel strategies consisting in developing allosteric modulators (AMs), biased ligands (BLs), or antibodies (Abs) are now emerging. These new classes of ligands are associated with advantages for the development of safer therapeutics but their identification can also prove to be challenging and novel screening paradigms are required. This chapter discusses these novel approaches for AM and BL identification and the recent identification of Abs showing AM/BL properties. Taken together, these new paradigms mark the beginning of a new GPCR drug discovery age.