GPCRs proximally engage G proteins and β-arrestins to relay various effects at the receptor, cellular and physiologic levels. Recent drug discovery efforts have focused on the preferential engagement of either G proteins or β-arrestins to exert specific signaling outcomes. However, several studies have begun to highlight the complex interplay between G proteins and β-arrestins that complicate our understanding of these signaling paradigms. Thus, this session will highlight the latest concepts with regard to the ligand bias and the molecular relationship between G proteins and β-arrestins, as well as their application to relevant cell types and desired therapeutic outcomes.