G-protein-mediated signaling is the most widely used signaling mechanism in cells and its regulation is crucial for various physiological functions. G-protein-coupled receptor (GPCR) kinases (GRKs) are involved in the desensitization of GPCR signals. Recently, the X-ray crystal structure of GRK2 complexed with G beta gamma was demonstrated and revealed the intimate association of three important signaling modules with G beta gamma to regulate GRK2 activity.