Heart failure (HF) is a complex syndrome affecting millions of people around the world. Over the past decade, the therapeutic potential of targeting epigenetic regulators in HF has been discussed extensively. Recent advances in next-generation sequencing techniques have contributed substantial progress in our understanding of the role of DNA methylation, post-translational modifications of histones, adenosine triphosphate (ATP)-dependent chromatin conformation and remodeling, and non-coding RNAs in HF pathophysiology. In this review, we summarize epigenomic studies on human and animal models in HF.