Covalent modification of DNA, such as cytosine methylation, can induce heritable gene silencing. If epigenetic modifications can be specifically targeted, new approaches to transcriptional therapy should result. To address this challenge we sought to design methyltransferases that would act only at a desired site by adapting the sequence-enabled assembly strategy. Our split DNA methylase performed site-specific CpG methylation in living cells without any background methylation when appropriately assembled at the target site. This is the first successful application of the sequence-enable enzyme reassembly approach in vivo. This split-enzyme reassembly strategy will allow creation of programmable zinc finger methylases that act at any specific CpG site in the mammalian genome. Programmable methylases should orchestrate heritable gene silencing and should find application in DNA tagging approaches and in nanotechnology.