A cellular target of adenovirus E1A oncoprotein, p300 is a transcriptional coactivator required for the maintenance of differentiated phenotypes in cardiac myocytes. The full transcriptional activities of hypertrophy-responsive transcription factors such as GATA-4 and MEF2 require interaction with p300. A p300 protein also possesses intrinsic histone acetyl transferase activity, which promotes a transcriptionally active chromatin configuration. Here, we review the biological functions of p300 in cardiac myocytes. Although p300 is biologically active in many cell types, this protein appears to play a crucial role in the differentiation, growth and apoptosis of cardiac myocytes. Understanding precise mechanisms of its biological functions will shed light on molecular pathways for heart failure.