Cardiac function is dynamically regulated by various G protein-coupled receptors (GPCRs). GPCR kinases (GRKs) are important in cardiac GPCR regulation through phosphorylation and desensitization of these receptors. GRK2 and GRK5 are the predominant GRKs in the heart, and the most widely characterized as they are both up-regulated in the failing heart. Prior studies from our Lab have determined that GRK5 plays a crucial role in pathological cardiac hypertrophy. Another type of hypertrophy termed, “physiological hypertrophy” occurs with exercise training and is defined as an enlargement in cardiac myocyte size leading to favorable cardiac adaptations. At present, it is unclear if GRK5 is a regulator of physiological hypertrophy in addition to its role in maladaptive hypertrophy. We hypothesize that GRK5 will not regulate physiological hypertrophy such that mice with cardiac-specific overexpression of GRK5 (TgGRK5) will yield a similar post-exercise cardiac physiological hypertrophic response as that of control wild-type (WT) mice. To test this hypothesis, TgGRK5 and WT mice were exposed to a 21 day high-intensity swimming exercise protocol. For each line, sham mice, which did not swim served as appropriate controls. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured. TgGRK5 and WT mice both exhibited a characteristic 10-15% increase in HW/BW and HW/TL ratios, which are standard measures of cardiac hypertrophy. In addition, hearts were sectioned and H&E stained to evaluate myocyte size. Both TgGRK5 and WT mice exhibited a significant increase in myocyte size. Cardiac function was evaluated via echocardiography both prior to and after exercise training, and no changes were observed between TgGRK5 and WT mice after training. These data were re-affirmed in H9C2 cells and neonatal rat ventricular myocytes overexpressing either GFP or GRK5, which exhibited similar increases in cell size and AKT phosphorylation after IGF-1 treatment, a physiological hypertrophy stimulus. Taken together, these data suggest that physiological hypertrophy is similar in both control and TgGRK5 mice, confirming that GRK5 is solely a regulator of pathological cardiac hypertrophy.