G‐protein‐coupled receptor kinase 2 (GRK2) is a central regulator of G‐protein‐coupled receptor signaling. We report that Mdm2, an E3‐ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by β₂‐adrenergic receptor stimulation and β‐arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2‐deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin‐like growth factor‐1 alters Mdm2‐mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions.