Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy.