DNA methylation plays a central role in the epigenetic regulation of gene expression during development and disease. Remarkably, the complex and changing patterns of genomic DNA methylation are established and maintained by only three DNA methyltransferases. Here we focus on DNMT1, the major and ubiquitously expressed DNA methyltransferase in vertebrates, to outline possible regulatory mechanisms. A list of all protein interactions and post-translational modi!cations reported for DNMT1 clearly shows that DNMT1, and by extension also DNA methylation in general, are functionally linked with several other epigenetic pathways and cellular processes. General themes of these interactions and modi!cations include the activation, stabilization and recruitment of DNMT1 at speci!c sites and heterochromatin regions. For a comprehensive understanding of the regulation of DNA methylation it is now necessary to systematically quantify the interactions and modi!cations of DNMT1, to elucidate their function at the molecular level and to integrate these data at the cellular level.