The idea that a receptor works like an on-off switch that is flipped by ligand binding has given way to a realization that a receptor-ligand interaction is something more like a handshake that can send many signals, ranging from clammy, weak, and indecisive to firm, extroverted, and confident. This is particularly true of the β2-adrenergic receptor (β2AR), a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor that has two primary modes of signaling—activation of adenylyl cyclase either through the G protein Gs or through an internalization-dependent process that requires β-arrestins and leads to activation of mitogen-activated protein kinases. These signaling pathways can be differentially triggered by various pharmacological agonists, which appear to cause the receptor to adopt distinct conformations that can modify the signals emanating from the receptor. The two physiological ligands of the β2AR are epinephrine and norepinephrine, and in keeping with their distinct physiological functions, these agonists produce different signaling outputs from the receptor. Reiner et al. explored whether binding of these natural ligands also produces distinct conformations of the receptor. They used a combination of methods to monitor receptor structure, internalization, and biochemical activity. Receptor conformation was followed through fluorescence resonance energy transfer (FRET) between probes linked to the third intracellular loop and the C terminus of the receptor, the former being a region critical for activation of G proteins by the receptor. Their results showed that the receptor indeed has a sophisticated sense of “touch” that interprets the nature of its interacting ligand. Norepinephrine produced a smaller and slower FRET signal than did epinephrine, but G protein activation by the two ligands was similar, indicating that there may be an amplification step between the receptor and activation of adenylyl cyclase. This could reflect catalytic activation of multiple G proteins by the receptors, for example. On the other hand, the synthetic partial agonist terbutaline gave both weaker FRET signals and weaker activation of adenylyl cyclase. The authors also monitored association of β-arrestin with the receptor and found that norepinephrine was weaker at promoting this receptor signaling event. There were further subtle differences as well. Although all the agonists tested enhanced association of β-arrestin with the receptor with similar kinetics after a pulse of the ligand, a slower and smaller response was induced by norepinephrine. Norepinephrine thus appears to be more tightly coupled to activation of Gs rather than the other receptor-initiated events. The authors also conclude that the movements of the receptor cannot be fully resolved by the FRET sensor linked to the G protein activation site. Perhaps future studies may allow definition of the particular movements that result in β-arrestin association, internalization, and activation of G-protein–coupled receptor kinases.