G-protein-coupled receptors are fundamental signaling proteins whose responsiveness must be tightly regulated to maintain cellular homeostasis and prevent overstimulation. This process, known as desensitization, involves an adaptive mechanism that is initiated mainly by the rapid uncoupling of the active receptor from its heterotrimeric G protein. The key molecular steps involve the phosphorylation of the agonist-bound receptor, typically at intracellular serine and threonine residues, by G-protein-coupled receptor kinases (GRKs), with secondary messenger kinases, such as protein kinase A (PKA), also contributing to this process (heterologous desensitization). This significantly increases the receptor’s affinity for β-arrestins. Following its interaction, β-arrestins physically block further G-protein interaction, which terminates the signal, and act as scaffolding proteins to recruit clathrin and adaptor protein complex AP2. The latter complex facilitates receptor sequestration into clathrin-coated pits that are subsequently pinched off by the GTPase Dynamin. In this way, internalized receptors sorted in early endosomes are driven toward one of two pathways. Rapid dephosphorylation promotes recycling back to the plasma membrane, resensitization, while sustained phosphorylation targets the receptors for lysosomal degradation and downregulation. Moreover, β-arrestins can initiate G-protein-independent signaling pathways from the endosome, including the MAPK cascade, demonstrating that desensitization is a dynamic and multifunctional regulatory network that controls signal termination, compartmentalized signaling, and receptor surface availability.