The regulatory networks governing gene expression in cardiomyocytes are under intense investigation, not least because dysregulation of the gene programme has a fundamental role in the development of a failing myocardium. Epigenetic modifications and functional non-protein-coding RNAs (ncRNAs) are important contributors to this process. The epigenetic modifications that regulate transcription comprise post-translational changes to histones—the proteins around which DNA is wound—as well as modifications to cytosine residues on DNA. The most studied of the histone changes are acetylation and methylation. Histone acetylation is known to be important in cardiac physiology and pathophysiology, but the roles of other histone modifications and of cytosine methylation are only starting to be investigated. Understanding of the role of microRNAs has also seen major advancements, but the function of long ncRNAs is less well defined. Moreover, the connection between ncRNAs and epigenetic modifications is poorly understood in the heart. In this Review, we summarize new insights into how these two layers of gene-expression regulation might be involved in the pathogenesis of cardiac hypertrophy and failure, and how we are only beginning to appreciate the complexity of the interactive network of which they are part.