Highlights: [•] Biased ligands stabilize subsets of receptor conformations to engage unique pharmacology. [•] Biased ligands may reduce on-target adverse effects or engender novel pharmacology. [•] TRV027, in clinical trials for the treatment of acute heart failure, illustrates differentiation of a β-arrestin-biased ligand at the angiotensin II type 1 receptor. [•] TRV130, in clinical development for the management of pain, illustrates differentiation of a G-protein-biased ligand at the μ opioid receptor. [ABSTRACT FROM AUTHOR]