Lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) are involved in the regulation of lysine acetylation, a conserved post-translational protein modification that is an important modulator of cardiac metabolism. Li and colleagues describe the complex roles of KATs and KDACs in both the normal and diseased heart and provide an overview of the evidence indicating a therapeutic role of KDAC inhibitors in cardiovascular disease.