M ethylation of DNA at cytosine residues is a heritable, epigenetic modification that is critical for proper regulation of gene expression, genomic imprinting, and mammalian development. 5-m ethylcytosine is a repressive epigenetic mark established de novo by two enzymes, DNMT3a and DNMT3b, and is maintained by DNMT1. 5-m ethylcytosine was originally thought to be passively depleted during DNA replication. However, subs equent studies have shown that Ten-Eleven Translocation (TET) proteins TET1, TET2, and TET3 can catalyze the oxidation of me thylated cytosine to 5-hydroxym ethylcytosine (5-hmC). Additionally, TET proteins can further oxidize 5-hmC to form 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), both of which are excised by thymine-DNA glycosylase (TDG), effectively linking cytosine oxidation to the base excision repair pathway and supporting active cytosine deme thylation. Normally DNA m ethylation occurs in a bimodal fashion, such that CpG dinucleotides are largely m ethylated across the genome, except in short stretches of CpG-rich sequences associated with gene promoters, known as CpG-islands, where m ethylation is virtually abs ent. Cancer cell genomes often undergo global hypom ethylation, while CpG-islands become hyperm ethylated, causing their associated promoters to become repressed. There is evidence that a number of aberrantly hyperm ethylated CpG-islands found in carcinomas occur at tumor suppressor genes such as RB1, MLH1, and BRCA1.