Myeloid hematological malignancies are among the epigenetically best characterized neoplasms. The comparatively low number of recurring balanced and unbalanced chromosomal abnormalities as well as common genetic mutations has enabled scientists to relate epigenetic states to these. The ease of accessing malignant cells through bone marrow aspiration has certainly contributed to the fast expansion of knowledge. Even so, the clinical and pathogenetic relevance of epigenetic changes is still not known, and the field will certainly evolve very fast with the development of new analytic techniques. The first example of successful epigenetic therapy is seen in myeloid malignancies, in the high-risk myelodysplastic syndromes (MDS) which are routinely treated with the demethylating agent azacytidine.This chapter will concentrate on describing the epigenetic changes in acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and MDS. An overview of clinical relevance and epigenetic therapeutic approaches is also made.