G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and play a critical role in mammalian physiology. Traditionally, GPCR signaling was thought to occur exclusively at the cell surface, but recent evidence suggests that receptors can also activate G proteins from intracellular compartments, leading to unique cellular responses. This review discusses the current understanding of compartmentalized GPCR signaling and its regulatory mechanisms. The classical model of GPCR signaling involves the activation of G proteins at the cell surface, which then stimulate second messengers like cyclic AMP (cAMP) or calcium. However, emerging evidence indicates that GPCRs can also activate G proteins in endosomes, Golgi, and other intracellular compartments. This intracellular signaling can lead to distinct cellular functions, such as protein phosphorylation and transcriptional reprogramming. Key mechanisms that regulate intracellular GPCR signaling include the presence of specific biochemical complexes (e.g., PDEs, ACs, arrestins, retromer) and unique biophysical properties of intracellular compartments. For example, the early endosome, a well-characterized signaling compartment, is enriched in certain AC isoforms and has a slightly acidic pH, which can influence GPCR activity. Additionally, the size and lipid composition of intracellular compartments can impact GPCR signaling dynamics. The evolution of compartmentalized GPCR signaling may serve to regulate the fidelity and robustness of stimulus detection. For instance, intracellular signaling can mediate pathway specificity by distinguishing between different ligands or stimulus strengths. Weak receptor stimulation may trigger quick cellular adaptations, while strong stimulation can initiate a second wave of signaling via intracellular compartments. Despite the growing understanding of compartmentalized GPCR signaling, many aspects remain to be explored. Further research is needed to establish the molecular, cellular, and physiological relevance of intracellular GPCRs and to understand the regulatory mechanisms that shape spatially encoded outcomes. This knowledge could inform the development of more selective interventions targeting these pathways for therapeutic purposes.G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and play a critical role in mammalian physiology. Traditionally, GPCR signaling was thought to occur exclusively at the cell surface, but recent evidence suggests that receptors can also activate G proteins from intracellular compartments, leading to unique cellular responses. This review discusses the current understanding of compartmentalized GPCR signaling and its regulatory mechanisms. The classical model of GPCR signaling involves the activation of G proteins at the cell surface, which then stimulate second messengers like cyclic AMP (cAMP) or calcium. However, emerging evidence indicates that GPCRs can also activate G proteins in endosomes, Golgi, and other intracellular compartments. This intracellular signaling can lead to distinct cellular functions, such as protein phosphorylation and transcriptional reprogramming. Key mechanisms that regulate intracellular GPCR signaling include the presence of specific biochemical complexes (e.g., PDEs, ACs, arrestins, retromer) and unique biophysical properties of intracellular compartments. For example, the early endosome, a well-characterized signaling compartment, is enriched in certain AC isoforms and has a slightly acidic pH, which can influence GPCR activity. Additionally, the size and lipid composition of intracellular compartments can impact GPCR signaling dynamics. The evolution of compartmentalized GPCR signaling may serve to regulate the fidelity and robustness of stimulus detection. For instance, intracellular signaling can mediate pathway specificity by distinguishing between different ligands or stimulus strengths. Weak receptor stimulation may trigger quick cellular adaptations, while strong stimulation can initiate a second wave of signaling via intracellular compartments. Despite the growing understanding of compartmentalized GPCR signaling, many aspects remain to be explored. Further research is needed to establish the molecular, cellular, and physiological relevance of intracellular GPCRs and to understand the regulatory mechanisms that shape spatially encoded outcomes. This knowledge could inform the development of more selective interventions targeting these pathways for therapeutic purposes.