Metastatic progression is strongly influenced by the connection between hyperactivated signaling pathways. G-protein coupled receptors (GPCRs) through β-arrestins (β-arrs), which serve as intracellular signaling molecules, integrate different pathways to control multiple aspects of metastatic process. As primary component of a core-scaffold, β-arr-dependent signaling represents a mean to direct spatiotemporal specificity of multi-protein complexes in invasion and extracellular matrix (ECM) degradation. Under this paradigm, β-arrs engage a growing number of signaling molecules and organizing protein networks controlling multiple pathways, and cytoskeleton modifications, permitting adaptation to the tumor microenvironment to sustain metastatic dissemination. These findings implicate GPCR/β-arr function as a regulatory tethering hub to orchestrate diverse cellular mechanisms of cancer cell migration and invasion that are critical for metastatic progression. In this chapter, we outline the most recent findings on GPCR/β-arr-guided molecular interactions in specific intracellular compartments to drive metastasis, while discussing new perspectives for the selection of most effective therapeutic options for a personalized medicine.