Pathological remodelling of the myocardium, including inflammation, fibrosis and hypertrophy, in response to acute or chronic injury is central in the development and progression of heart failure (HF). While both resident and infiltrating cardiac cells are implicated in these pathophysiological processes, recent evidence has suggested that endothelial cells (ECs) may be the principal cell type responsible for orchestrating pathological changes in the failing heart. Epigenetic modification of nucleic acids, including DNA, and more recently RNA, by methylation is essential for physiological development due to their critical regulation of cellular gene expression. As accumulating evidence has highlighted altered patterns of DNA and RNA methylation in HF at both the global and individual gene levels, much effort has been directed towards defining the precise role of such cell-specific epigenetic changes in the context of HF. Considering the increasingly apparent crucial role that ECs play in cardiac homeostasis and disease, this article will specifically focus on nucleic acid methylation (both DNA and RNA) in the failing heart, emphasising the key influence of these epigenetic mechanisms in governing EC function. This review summarises current understanding of DNA and RNA methylation alterations in HF, along with their specific role in regulating EC function in response to stress (e.g. hyperglycaemia, hypoxia). Improved appreciation of this important research area will aid in further implicating dysfunctional ECs in HF pathogenesis, whilst informing development of EC-targeted strategies and advancing potential translation of epigenetic-based therapies for specific targeting of pathological cardiac remodelling in HF.