Research over the past decade has confirmed that epigenetic alterations act in concert with genetic lesions to deregulate gene expression in acute myeloid leukemia and myelodysplastic syndromes. Epigenetic alterations may serve as markers of disease, and may potentially be used for classification, prognostication and to monitor minimal residual disease. In addition, we now have the capability to pharmaceutically target epigenetic modifications, and there is an urgent need for early validation of the efficacy of the drugs. Also, an improved understanding of the functionality of epigenetic modifications may further pave the road towards individualized therapy. The recent advances in biotechnology and bioinformatics provide a plethora of novel tools for characterizing the epigenome in clinical samples, but at this point the practical, clinical utility of these methodologies needs further exploration. Here, we provide the pros and cons of the currently most feasible methods used for characterizing the methylome in clinical samples, and give a brief introduction to novel approaches to sequencing that may revolutionize our abilities to characterize the genomes and epigenomes in acute myeloid leukemia and myelodysplastic syndrome patients.