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Chromatin modifications at both histones and DNA are critical for regulating gene expression. Mis-regulation of such epigenetic marks can lead to pathological states; indeed, cancer affecting the hematopoietic system is frequently linked to epigenetic abnormalities. Here, we discuss the different types of modifications and their general impact on transcription, as well as the polycomb group of proteins, which effect transcriptional repression and are often mis-regulated. Further, we discuss how chromosomal translocations leading to fusion proteins can aberrantly regulate gene transcription through chromatin modifications within the hematopoietic system. PML–RARa, AML1–ETO and MLL-fusions are examples of fusion proteins that mis-regulate epigenetic modifications (either directly or indirectly), which can lead to acute myeloblastic leukemia (AML). An in-depth understanding of the mechanisms behind the mis-regulation of epigenetic modifications that lead to the development and progression of AMLs could be critical for designing effective treatments.