G protein-coupled receptors (GPCRs) are key regulators of cellular signaling. Receptor desensitization, the process by which GPCRs become less responsive to continuous stimulation, is a critical aspect of GPCR function. This review discusses the roles of receptor kinases and β-arrestins in GPCR signaling and desensitization. Traditional views of desensitization as a process opposing activation have been challenged by new insights showing that desensitization and activation are closely linked aspects of GPCR function. Three families of regulatory molecules are involved in GPCR desensitization: second messenger-regulated kinases (e.g., PKA and PKC), G protein-coupled receptor kinases (GRKs), and β-arrestins. GRKs phosphorylate GPCRs, which then bind β-arrestins, leading to receptor internalization and desensitization. β-arrestins also play a role in receptor endocytosis, which is essential for receptor resensitization and dephosphorylation. Recent studies have shown that β-arrestins and GRKs are not only involved in desensitization but also in signaling pathways, such as MAP kinase activation. The internalization of GPCRs via clathrin-coated vesicles is crucial for these processes. Additionally, β-arrestins can mediate the internalization of GPCRs, which is necessary for their dephosphorylation and resensitization. The role of β-arrestins in GPCR signaling is further highlighted by their ability to regulate the internalization of GPCRs and their subsequent signaling. β-arrestins can also influence the coupling of GPCRs to different G proteins, thereby switching signaling pathways. GRKs have been shown to phosphorylate not only GPCRs but also other proteins, such as tubulin, suggesting a broader role in cellular signaling. The regulation of GRK activity is influenced by various factors, including the binding of their substrates. Overall, the understanding of GPCR signaling and desensitization is evolving, with new evidence showing that molecules previously viewed as solely involved in desensitization also play crucial roles in signaling. This highlights the complexity of GPCR function and the importance of β-arrestins and GRKs in both desensitization and signaling processes.G protein-coupled receptors (GPCRs) are key regulators of cellular signaling. Receptor desensitization, the process by which GPCRs become less responsive to continuous stimulation, is a critical aspect of GPCR function. This review discusses the roles of receptor kinases and β-arrestins in GPCR signaling and desensitization. Traditional views of desensitization as a process opposing activation have been challenged by new insights showing that desensitization and activation are closely linked aspects of GPCR function. Three families of regulatory molecules are involved in GPCR desensitization: second messenger-regulated kinases (e.g., PKA and PKC), G protein-coupled receptor kinases (GRKs), and β-arrestins. GRKs phosphorylate GPCRs, which then bind β-arrestins, leading to receptor internalization and desensitization. β-arrestins also play a role in receptor endocytosis, which is essential for receptor resensitization and dephosphorylation. Recent studies have shown that β-arrestins and GRKs are not only involved in desensitization but also in signaling pathways, such as MAP kinase activation. The internalization of GPCRs via clathrin-coated vesicles is crucial for these processes. Additionally, β-arrestins can mediate the internalization of GPCRs, which is necessary for their dephosphorylation and resensitization. The role of β-arrestins in GPCR signaling is further highlighted by their ability to regulate the internalization of GPCRs and their subsequent signaling. β-arrestins can also influence the coupling of GPCRs to different G proteins, thereby switching signaling pathways. GRKs have been shown to phosphorylate not only GPCRs but also other proteins, such as tubulin, suggesting a broader role in cellular signaling. The regulation of GRK activity is influenced by various factors, including the binding of their substrates. Overall, the understanding of GPCR signaling and desensitization is evolving, with new evidence showing that molecules previously viewed as solely involved in desensitization also play crucial roles in signaling. This highlights the complexity of GPCR function and the importance of β-arrestins and GRKs in both desensitization and signaling processes.