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The manipulation of chromatin structure regulates gene expression and the flow of genetic information. Histone modifications and ATP-dependent chromatin remodeling together with DNA methylation are dynamic processes that modify chromatin architecture and profoundly modulate gene expression. Their coordinated control is key to ensuring proper cell commitment and organ development, as well as adaption to environmental cues. Recent studies indicate that abnormal epigenetic status of the genome, in concert with alteration of transcriptional networks, contribute to the development of adult cardiomyopathy such as pathological cardiac hypertrophy. Here we consider the emerging role of different classes of chromatin regulators and how their dysregulation in the adult heart alters specific gene programs with subsequent development of major cardiomyopathies. Understanding the functional significance of the different epigenetic marks as points of genetic control may represent a promising future therapeutic tool. © 2013 King Faisal Specialist Hospital & Research Centre. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.