Amoebiasis is a serious infectious disease that is caused by the unicellular parasite, Entamoeba histolytica. This parasite is mainly found in developing countries, and are named owing to its ability to destroy tissues. The molecular mechanisms that regulate the virulence of this parasite are not well understood. In recent years, an increasing interest in the epigenetic regulation of the parasite's virulence has emerged. In this article, an overview of our current knowledge about the role of DNA methylation, histone modifications and RNA-associated silencing in the biology of E. histolytica is provided. The relevance of some features of the parasite's unique epigenetic machinery to the development of new antiamoebic therapeutic molecules is discussed.