Epigenetic deregulation is now a well-recognized although not yet fully understood mechanism that contributes to the development and progression of myeloid malignancies. In the past 15 years, next-generation sequencing studies have revealed patterns of aberrant DNA methylation, altered chromatin states, and mutations in chromatin modifiers across the spectrum of myeloid malignancies. Studies into the mechanisms that drive these diseases through mouse modeling have helped identify new avenues for therapeutic interventions, from initial treatment to resistant or relapsed disease. This is particularly significant when chemotherapy with cytotoxic agents remains the general standard of care. In this review, we will discuss some of the recent findings of epigenetic mechanisms and how these are informing the development of more targeted strategies for therapeutic intervention in myeloid malignancies.