The genesis of designing bivalent or bitopic molecules that engender unique pharmacological properties began with Portoghese's work directed toward opioid receptors, in the early 1980s. This strategy has evolved as an attractive way to engineer highly selective compounds for targeted G-protein coupled receptors (GPCRs) with optimized efficacies and/or signaling bias. The emergence of X-ray crystal structures of many GPCRs and the identification of both orthosteric and allosteric binding sites have provided further guidance to ligand drug design that includes a primary pharmacophore (PP), a secondary pharmacophore (SP), and a linker between them. It is critical to note the synergistic relationship among all three of these components as they contribute to the overall interaction of these molecules with their receptor proteins and that strategically designed combinations have and will continue to provide the GPCR molecular tools of the future.