The increasing depth of knowledge about cancer biology throughout the last decades, has underlined the importance of not only genetic aberrations, but also epigenetic abnormalities in cancer cells. The extensive exploration of the cancer epigenome has provided insights into key pathways involved in tumorigenesis, as well as has allowed the development of novel epigenetic therapies. In this review, we will present the important role of epigenetic alterations in hematological diseases, with special focus on epigenetically-based targeting of hematological malignancies.