Vertebrate genomes are highly methylated at cytosine residues in CpG sequences. CpG methylation plays an important role in epigenetic gene silencing and genome stability. Compared with other epigenetic modifications, CpG methylation is thought to be relatively stable; however, it is sometimes affected by environmental changes, leading to epigenetic instability and disease. CpG methylation is reversible and regulated by DNA methyltransferases and demethylases including ten-eleven translocation. Here, we discuss CpG methylation instability and the regulation of CpG methylation by DNA methyltransferases and ten-eleven translocation in pluripotent stem cells.