This review by Robert J. Lefkowitz discusses the new roles of receptor kinases and β-arrestins in receptor signaling and desensitization. It highlights how these molecules, traditionally viewed as primarily involved in desensitization, are now recognized as crucial for receptor signaling and rapid control of receptor function. The review covers established paradigms such as the role of second messenger kinases (e.g., PKA and PKC) and GRKs (e.g., βARK) in receptor desensitization, and the mechanisms of receptor endocytosis and resensitization. It also explores novel paradigms, including the role of β-arrestins and GRKs in receptor endocytosis, the involvement of GRKs and β-arrestins in mitogenic signaling, and the cAMP-dependent protein kinase's ability to switch signaling pathways. The review concludes by suggesting that current concepts of GPCR signaling and desensitization are evolving, with previously desensitizing molecules playing important signaling roles.This review by Robert J. Lefkowitz discusses the new roles of receptor kinases and β-arrestins in receptor signaling and desensitization. It highlights how these molecules, traditionally viewed as primarily involved in desensitization, are now recognized as crucial for receptor signaling and rapid control of receptor function. The review covers established paradigms such as the role of second messenger kinases (e.g., PKA and PKC) and GRKs (e.g., βARK) in receptor desensitization, and the mechanisms of receptor endocytosis and resensitization. It also explores novel paradigms, including the role of β-arrestins and GRKs in receptor endocytosis, the involvement of GRKs and β-arrestins in mitogenic signaling, and the cAMP-dependent protein kinase's ability to switch signaling pathways. The review concludes by suggesting that current concepts of GPCR signaling and desensitization are evolving, with previously desensitizing molecules playing important signaling roles.