Epigenetic regulatory mechanisms play key roles in cardiac development, differentiation, homeostasis, response to stress and injury, and disease. Human heart failure (HF) epigenetic regulatory mechanisms have not been deciphered to date. This 2-part review distills the rapidly evolving research focused on human HF epigenetic regulatory mechanisms. Part I, which was published in the September/October issue, focused on epigenetic regulatory mechanisms involving RNA, specifically the role of short, intermediate, and long noncoding RNAs (lncRNAs) and endogenous competing RNA regulatory networks. Part II, now in the November/December issue, focuses on the epigenetic regulatory mechanisms involving DNA, including DNA methylation, histone modifications, and chromatin conformational changes. Part II concludes with 2 examples of well-studied integrated epigenetic regulatory mechanisms: the structural and functional roles of the Mediator complex in regulating transcription and the epigenetic networked "cross-talk" regulating atrial natriuretic peptide and brain natriuretic peptide promoter activation.