The term 'epigenetic' fuses old and new concepts that refer to the modulation of gene expression in cellular heritability, fate, development and programming-reprogramming other than the DNA sequence itself. Epigenetic control of transcription is regulated by enzymes that mediate covalent modifications at gene-regulatory regions and histone proteins around which chromosomal DNA is wound. Many of the enzymes that mediate chromatin epigenetic reactions are deregulated in diseases such as cancer. Thus, small-molecule inhibitors that target chromatin-modifying enzymes represent a novel option for treatment, and DNA methyltransferase and histone deacetylase inhibitors have been approved for cancer treatment. Moreover, other classes of epi-enzymes (MS-275, SAHA) have been demonstrated to have strong disease association, and are currently being targeted for modulation. An epigenetic poly-pharmacological approach targeting multiple chromatin-modifying enzymes may represent a 'smart' option to treat cancer versus the current view on the selective and single pharmacological targeting of epigenetic enzymes.