Histones control gene expression by modulating the structure of chromatin and the accessibility of regulatory DNA sequences to transcriptional activators and repressors. Posttranslational modifications of histones have been proposed to establish a “code” that determines patterns of cellular gene expression. Acetylation of histones by histone acetyltransferases stimulates gene expression by relaxing chromatin structure, allowing access of transcription factors to DNA, whereas deacetylation of histones by histone deacetylases promotes chromatin condensation and transcriptional repression. Recent studies demonstrate histone acetylation/deacetylation to be a nodal point for the control of cardiac growth and gene expression in response to acute and chronic stress stimuli. These findings suggest novel strategies for “transcriptional therapies” to control cardiac gene expression and function. Manipulation of histone modifying enzymes and the signaling pathways that impinge on them in the settings of pathological cardiac growth, remodeling, and heart failure represents an auspicious therapeutic approach.