Alterations in the genome and the epigenome are common in most cancers. Changes in epigenetic signatures, including aberrant DNA methylation and histone deacetylation, are among the most prevalent modifications in cancer and lead to dramatic changes in gene expression patterns. Because DNA methylation and histone deacetylation are reversible processes, they have become attractive as targets for cancer epigenetic therapy, both as single agents and as 'enhancing' agents for other treatment strategies. In this review we discuss our current view of the mammalian epigenome, this view has changed over the years because of the availability of novel technologies. We further demonstrate how the profound understanding of epigenetic alterations in cancer will help develop novel strategies for epigenetic therapies.