G protein-coupled receptors (GPCRs) located at the cell surface bind extracellular ligands and convey intracellular signals via activation of heterotrimeric G proteins. Traditionally, G protein signaling was viewed to occur exclusively at this subcellular region followed by rapid desensitization facilitated by β-arrestin-mediated G protein uncoupling and receptor internalization. However, emerging evidence over the past 15 years suggests that these β-arrestin-mediated events do not necessarily terminate receptor signaling and that some GPCRs continue to activate G proteins after having been internalized into intracellular compartments such as endosomes. In this talk I will explore mechanisms that regulate not only the location of G proteins activation, but also the duration. I will also discuss the physiological implications of spatiotemporal GPCR signaling, with a particular focus on chemokine receptors.