The transmission of information through G-protein-coupled receptor (GPCR)-initiated signaling pathways is modulated in several ways. Although phosphorylation of some of the proteins that populate these pathways is a well-known modulatory process, recent studies have shown that signaling proteins can also undergo regulated ubiquitination in response to GPCR activation, with diverse consequences. To date, three GPCRs, some of their associated proteins and certain downstream mediators, notably inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] receptors, have been shown to be ubiquitinated following GPCR activation. Regulated ubiquitination causes proteasomal degradation of Ins(1,4,5)P₃ receptors and appears to control GPCR endocytosis and trafficking. Defining the roles of ubiquitination in GPCR-mediated signaling is an important task because novel drugs that perturb the ubiquitin–proteasome pathway are now being approved as therapeutic agents.