G protein-coupled receptors (GPCRs) make up the largest and most diverse family of membrane receptors in the human genome, relaying information about the presence of diverse extracellular stimuli to the cell interior. All known GPCRs share a common architecture of seven membrane-spanning helices connected by intra- and extracellular loops. Most GPCR-mediated cellular responses result from the receptor acting as a ligand-activated guanine nucleotide exchange factor for heterotrimeric guanine nucleotide-binding (G) proteins whose dissociated subunits activate effector enzymes or ion channels. GPCR signaling is subject to extensive negative regulation through receptor desensitization, sequestration, and down regulation, termination of G protein activation by GTPase-activation proteins, and enzymatic degradation of second messengers. Additional protein-protein interactions positively modulate GPCR signaling by influencing ligand-binding affinity and specificity, coupling between receptors, G proteins and effectors, or targeting to specific subcellular locations. These include the formation of GPCR homo- and heterodimers, the interaction of GPCRs with receptor activity-modifying proteins, and the binding of various scaffolding proteins to intracellular receptor domains. In some cases, these processes appear to generate signals in conjunction with, or even independent of, G protein activation.