Crucial cellular events such as death, growth, metabolism, proliferation, and hypertrophy are regulated by phosphorylation and dephosphorylation of proteins. PH domain leucine-rich repeat protein phosphatase (PHLPP) is a serine/threonine phosphatase that has been shown to directly dephosphorylate several members of the AGC family of kinases. Removal of PHLPP2 in neonatal rat ventricular myocytes (NRVMs) induces hypertrophic growth and activates fetal gene expression at baseline and potentiates phenylephrine (PE)-induced gene expression 2 fold over siControl. Since removal of PHLPP2 in NRVMs does not affect Akt phosphorylation PHLPP2 must have the ability to repress cellular hypertrophy through regulation of other unknown targets. G-protein coupled receptor kinase 5 (GRK5), an AGC kinase, has been shown to regulate cardiac hypertrophy through de-repression of gene transcription and by directly binding DNA. Upon down-regulation of PHLPP2, stimulation of NRVMs with the hypertrophic agonist PE induced GRK5 accumulation in the nucleus and export of HDAC5. Conversely, overexpression of PHLPP2 blocked PE-induced hypertrophic growth, re-expression of fetal genes and nuclear accumulation of GRK5 in cardiomyocytes. The translocation of GRK5 by PHLPP2 knockdown was dependent on calmodulin binding. Through siRNA studies it was found that GRK5 is necessary for PE-induced hypertrophy following PHLPP2 knockdown. Here we demonstrate for the first time in cardiomyocytes that knockdown of PHLPP2 regulates hypertrophic growth through GRK5. Understanding the signaling pathways affected by PHLPP2 has potential for new therapeutic targets in the treatment of cardiac hypertrophy and failure.