DNA hypermethylation at the CpG dinucleotides clustered in “islands” in the promoter regions of genes causes transcriptional repression through the remodelling of chromatin. Aberrant methylation patterns of tumor suppressor genes and their subsequent silencing constitute a common feature of many cancers. Thus, the search for drugs that interfere in methylation-mediated gene repression has become one of the major goals in the design of cancer therapies. The major actors in the mammalian methylation system are DNA-methyltransferases (DNMTs), and methyl-CpG-binding proteins (MBDs), which recognize methylated cytosine and recruit repressor complexes, including histone deacetylases (HDACs). In this context, two major groups of drugs can be distinguished. The first one is constituted by substances that inhibit the action of DNMTs, either competing with cytosine or with S-adenosylmethionine (SAM, AdoMet) or acting over the DNMTs themselves. The second group involves compounds that inhibit subunits of the repressor complexes, such as HDACs. In this manuscript we review these two different groups of drugs, discussing their properties and the side-efects that have been described (that occur by interference with other metabolic pathways). We also propose the logical pharmacological extension of these findings to design more specific and efective drugs for the prevention and treatment of human cancer.