Annual Review of Biophysics, Vol. 47

G protein–coupled receptors (GPCRs), which mediate processes as diverse as olfaction and maintenance of metabolic homeostasis, have become the single most effective class of therapeutic drug targets. As a result, understanding the molecular basis for their activity is of paramount importance. Recent technological advances have made GPCR structural biology increasingly tractable, offering views of these receptors in unprecedented atomic detail. Structural and biophysical data have shown that GPCRs function as complex allosteric machines, communicating ligand-binding events through conformational change. Changes in receptor conformation lead to activation of effector proteins, such as G proteins and arrestins, which are themselves conformational switches. Here, we review how structural biology has illuminated the agonist-induced cascade of conformational changes that culminate in a cellular response to GPCR activation.