Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutations (nucleotide changes, deletions, recombinations) nor cytogenetic abnormalities are as common in human tumors as DNA methylation alterations. The most studied change of DNA methylation in neoplasms is the silencing of tumor suppressor genes by CpG island promoter hypermethylation, which targets genes such as p16^INK4a, BRCA1, and hMLH1. There is a profile of CpG island hypermethylation according to the tumor type, and genes silent by methylation represent all cellular pathways. The introduction of bisulfite-PCR methodologies combined with new genomic approaches provides a comprehensive spectrum of the genes undergoing this epigenetic change across all malignancies. However, we still know very little about how this aberrant DNA methylation “invades” the previously unmethylated CpG island and how it is maintained through cell divisions. Furthermore, we should remember that this methylation occurs in the context of a global genomic loss of 5-methylcytosine (5mC). Initial clues to understand this paradox should be revealed from the current studies of DNA methyltransferases and methyl CpG binding proteins. From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively. Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high.