A few drugs acting on DNA methyltransferase and histone deacetylase enzymes have already received FDA approval, providing validation that pharmacological alteration of epigenetic modifications has tangible clinical benefit. However, the current generation of epigenetic drugs acts by inhibiting chromatin-modifying enzymes and, consequently, has nonspecific, pan-genomic effects. This is associated with a significant dose-limiting toxicity. Our lab is trying to identify the molecules and pathways driving cancer-specific epigenetic modifications. We expect that future generations of cancer epigenetic therapies will target these driver molecules and pathways, instead of the core epigenetic machinery itself (that are necessary to establish and maintain the epigenetic landscape of normal cells). The identification of these drug targets will allow more rational cancer epigenetic therapies, with increased efficiency and with fewer risks associated with the reactivation of developmental genes.