DNA methylation is an epigenetic mechanism that orchestrates many of the abnormal gene expression changes seen in cancer without altering the actual genomic DNA sequences. Emerging evidence support that aberrant DNA methylation is an archetypal hallmark of cancer, and hypermethylation-mediated inactivation of tumor suppressor genes as well as hypomethylation-mediated activation of prometastatic genes are common attributes of cancer cells. Since methylation of DNA is reversible, targeting the methylome may serve as a suitable anti-cancer strategy. Several epigenetic drugs especially the ones which target the key enzyme in DNA methylation process, the DNA-methyltransferases (DNMTs), have shown promising results in clinical trials. Two DNMT inhibitors, 5-azacytidine (Vidaza^®) and 5-aza-2′-deoxycytidine (Decitabine, Dacogen^®), have already been approved by the Food and Drug Administration (FDA) for treating several types of cancer. Nevertheless, targeting hypermethylation through the use of DNMT inhibitors can also activate several prometastatic genes apart from the activation of tumor suppressor genes. This may lead to metastasis which is the primary cause of morbidity and mortality associated with solid tumors like breast cancer. So the anti-cancer strategies require a balance between the activation of tumor suppressor genes and repression of prometastatic genes to collectively block tumor growth and metastasis. This review describes some of the common methylation abnormalities seen in promoters of cancer-associated genes, the mechanism of action of various hypermethylation and hypomethylation inhibitors, the potential benefits and challenges of using them as anti-cancer therapeutic agents in general and for patients with breast cancer in particular as monotherapy or in combination settings.