DNA methylation is the epigenetic modification, which introduces 5mC as fifth base onto DNA. As for the distribution of 5mCs, it is well known that they distribute themselves in a non-random fashion in genomic DNA so that methylation pattern is characterized by the presence of methylated cytosines on the bulk of DNA while the unmethylated ones are mainly located within particular regions termed CpG islands. These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes. Their unmethylated state, which is an essential condition for the correct expression of correlated genes, is paradoxical if one considers that these regions are termed CpG islands because they are particularly rich in this dinucleotide, which is the best substrate for enzymes involved in DNA methylation. Anomalous insertion of methyl groups in these regions generally leads to the lack of transcription of correlated genes. An interesting scientific problem is to clarify the mechanism(s) whereby CpG islands, which remain protected from methylation in normal cells, are susceptible to methylation in tumor cells. How the CpG moieties in CpG islands become vulnerable or resistant to the action of DNA methyltransferases and can thus lose or maintain their characteristic pattern of methylation is still an open question. Our aim is to gather some mechanisms regarding this intriguing enigma, which, despite all energy spent, still remains an unresolved puzzle.