Epigenetic modification of the genome is required for establishing lineage specific patterns of gene expression and is also essential for the maintenance of genomic stability. Methylation of most CpG dinucleotides within the genome is an important epigenetic mechanism. In most cell lineages, the reduction of methylation across the genome results in the derangement of gene expression, loss of genomic stability and P53-mediated cell death. By contrast, the generation of the pluripotent state within embryos requires the global loss of methylation from the genome. This global hypomethylation is a hallmark and unique feature of pluripotency. It occurs with the formation of each of the two pluripotent lineages within the embryo, the inner cell mass/epiblast and the primordial germ cells. Differentiation from the pluripotent state is characterized by the rapid return to a global hypermethylated state. The mechanisms and control of the dynamic changes that occur with entry of cells into pluripotency and their exit via differentiation will be considered in detail.