This review is provided in recognition of the extensive contributions of Dr. Robert J. Lefkowitz to the G protein-coupled receptor (GPCR) field and to celebrate his 75th birthday. Since one of the authors trained with Bob in the 80s, we provide a history of work done in the Lefkowitz lab during the 80s that focused on dissecting the mechanisms that regulate GPCR signaling, with a particular emphasis on the GPCR kinases (GRKs). In addition, we highlight structure/function characteristics of GRK interaction with GPCRs as well as a review of two recent reports that provide a molecular model for GRK-GPCR interaction. Finally, we offer our perspective on some future studies that we believe will drive this field. •GRKs mediate activation-dependent phosphorylation of GPCRs.•GRKs play a central role in switching GPCR signaling from G proteins to arrestins.•GRKs bind to multiple intracellular regions of the GPCR.•GRK binding promotes significant conformational changes that activate GRK activity.