Recent realization that plasma membrane G protein-coupled receptors (GPCRs) may translocate and establish ligand-responsive signaling complexes in other cellular structures has motivated studies of site-specific differences in transductional pathways. GPCRs and their ligands may signal transcription and other nuclear events by two basic mechanisms. The first consists of GPCR-complex activation of messengers that enter the nucleus and there initiate cell-modifying processes without the GPCR leaving the plasma membrane. The second encompasses entry into the nuclear membranes or matrix of either GPCR ligands, which bind to non-GPCR nuclear signaling proteins, proteolytic fragments of GPCRs capable of ligand-independent signaling, or intact GPCRs with transduction-competent factors that directly initiate or regulate transcriptional events. With the second mechanism, often concurrent down-regulation of plasma membrane GPCRs terminates signaling from the cell-surface and moves it into the nuclear domain. Site-dependent differences in signals from the same GPCR provide potentials for unique cellular abnormalities attributable to defective intracellular movement and distribution of a GPCR, site-specific alterations in ligand concentration, and limited intracellular bioavailability of pharmacological agents that can interact specifically with both nuclear and plasma membrane forms of a GPCR. Goetzl, E. J. Diverse pathways for nuclear signaling by G Protein-coupled receptors and their ligands.