Abstract Epigenetic mechanisms synergize with genetic alterations in modulating gene expression patterns in cancer cells. While epigenetic alterations are reversible genetic modifications are not. This has raised the attention of many groups to focus on a better understanding of the molecular mechanisms that underlie the establishment of altered DNA methylation, histone modifications patterns and miRNA expression. The improved understanding of these mechanisms we will in turn allow us to improve the strategies that can be used for epigenetic therapies. In this review we will discuss and summarize briefly our current knowledge of epigenetic alterations in leukemias and will turn our attention to a concrete example of epigenetic deregulation of CCAAT/enhancer-binding protein alpha ( C/EBPα ), a key regulator for granulocytic differentiation of common myeloid progenitor cells in order to highlight the cooperativity of genetic and epigenetic mechanisms acting on this gene during the process of leukemogenesis.