Recent pan-cancer studies have shown the importance of coupling DNA methylation patterns with transcriptome profiles to reveal tumor subgroups with clinically relevant distinct characteristics. While the coupling patterns remain in most cases matter for further study and/or interpretation, it is emerging that all associations between epigenetic changes and specific cancer histotypes can facilitate the development of novel epidrugs. In particular, together with chemotherapy and chemoprevention of cancer, these epidrugs will target specific enzymes involved in the complex regulation of gene expression. This perspective surveys recent cancer epigenetic findings on target drugs and therapeutic strategies, and focuses on the epigenetic modifications that can reverse a stable differentiated state of adult cell towards neoplastic phenotypes. The relevance of such developments may thus pave the way for patient’s customized personalized therapies.