THE ability of a system to regulate its responsiveness in the presence of a continuous stimulus, often termed desensitization, has been extensively characterized for the beta(2)-adrenergic receptor (beta(2)AR). beta(2)AR signalling is rapidly attenuated through receptor phosphorylation and subsequent binding of the protein beta-arrestin(1,2). Ultimately the receptor undergoes internalization(3,4), and although the molecular mechanism is unclear, receptor phosphorylation and beta-arrestin binding have been implicated in this process(5,6). Here we report that beta-arrestin and arrestin-3, but not visual arrestin, promote beta(2)AR internalization and bind with high affinity directly and stoichiometrically to clathrin, the major structural protein of coated pits, Moreover, beta-arrestin/arrestin chimaeras that are defective in either beta(2)AR or clathrin binding show a reduced ability to promote beta(2)AR endocytosis. Immunofluorescence microscopy of intact cells indicates an agonist-dependent colocalization of the beta(2)AR and beta-arrestin with clathrin, These results show that beta-arrestin functions as an adaptor in the receptor-mediated endocytosis pathway, and suggest a general mechanism for regulating the trafficking of G-protein-coupled receptors.