Methylation of DNA is a common epigenetic modification that plays an important role in the control of gene expression in mammalian cells. This process involves CpG dinucleotide sequences and is catalyzed by DNA-methyltransferase enzymes. Under physiological conditions, methylated CpG sites are only present in DNA sequences typical of bulk chromatin, where the DNA is inaccessible to transcription factors. In contrast, CpG islands of promoter regions are usually unmethylated (with few exceptions such as the genes on the inactive X-chromosome). DNA methylation abnormalities have recently emerged as the most frequent molecular changes in hematopoietic neoplasms. The authors of the present review are currently working in the field of myelodysplastic syndromes and secondary leukemias and have contributed original papers to peer-reviewed journals. The material analyzed in the present review includes articles and reviews published in journals covered by the Science Citation Index, and abstracts presented at recent international oncology and hematology meetings. Methylation and transcriptional status are inversely correlated, the hypermethylation of genes involved in cell-cycle control and apoptosis could have a pathogenetic role in the development of cancer. In particular, high-risk myelodysplastic syndromes (MDS) and secondary leukemias (SL) show a high prevalence of tumor-suppressor gene hypermethylation. The use of irreversible DNA methyltransferase inhibitors, such as 5-azacytidine and decitabine, appears to be a promising therapeutic option for the treatment of MDS and SL. Large clinical trials are still ongoing, but preliminary data recently published indicate for the first time that the natural history of MDS may be changed by a non-intensive treatment. Treatment with demethylating agents, 5-azacytidine and decitabine, at present results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival, when compared to supportive care. Azacytidine and decitabine provide a new treatment option, and should be the treatment choice for elderly patients with high risk MDS. It is whorty in fact that azacytidine and decitabine are especially active in patients with poor prognosis MDS. The combination with histone deacetylase inhibitors may increase the efficacy of hypomethylating agents in vivo.