Waning responsiveness to continuous or repeated stimulation constitutes the phenomenon of desensitization, which pervades biological systems. Over the last several years, molecular mechanisms for desensitization of cellular signaling through G protein-coupled receptors have been delineated, particularly at the level of the receptors themselves. This review focuses on those aspects of G protein-coupled receptor desensitization which occur within minutes of agonist exposure. Agonist-dependent desensitization of these receptors can reduce their signaling responsiveness to maximum stimulation by up to 70-80%; indeed, in some receptor systems, the process of receptor desensitization appears to effect the termination of the cellular signaling response. Agonist-induced desensitization involves phosphorylation of G protein-coupled receptors by two currently recognized classes of serine/threonine protein kinases. Second messenger-dependent kinases, phosphorylating a variety of proteins, mediate a generalized cellular hyporesponsiveness termed heterologous desensitization. G protein-coupled receptor kinases (GRKs) phosphorylate specifically agonist-occupied, or activated, receptors, and thereby initiate receptor-specific, or homologous, desensitization. GRK-mediated receptor phosphorylation facilitates the binding of an inhibitory arrestin protein to the phosphorylated receptor, an event which substantially impairs receptor signaling. The GRK family comprises six, and the arrestin family comprises four known members. Each GRK demonstrates the ability to phosphorylate a limited number of model receptor substrates, but the widespread expression of several GRKs and the two somatic arrestins suggest that GRK-initiated homologous desensitization is of general importance to a wide range of G protein-coupled receptors. Exploration of the substrate specificity for GRKs and the ligand specificity for arrestins remains in its early stages. Currently, GRKs can most readily be differentiated by the mechanisms each employs to associate with the plasma membrane. Accumulating data from human disease states and transgenic mice attest to the physiologic significance of GRK-initiated receptor desensitization.