BACKGROUND DNA methylation is a covalent modification of DNA, which plays a critical role in regulation of gene expression. Methyl marks in critical regulatory regions of genes silence gene expression. Two contrasting changes in DNA methylation were documented in cancers: regional hypermethylation of tumor suppressor genes and global hypomethylation. OBJECTIVE Most of the attention in the field has been directed toward the phenomenon of hypermethylation and silencing of tumor suppressor genes. Hypermethylation indeed plays an extremely important role in cancer and cancer progression. Nevertheless, hypomethylation is emerging now as a mechanism that might lead to activation of prometastatic genes in cancer. CONCLUSIONS Both methylation and demethylation could be pharmacologically modulated. It is argued here that inhibition of hypomethylation might provide a new therapeutic approach to antimetastatic therapy.