Epigenetic memory in the form of cytosine methylation is essential for vertebrate development and the formation of cellular identity (Lee, Hore and Reik, 2014). Active removal of DNA methylation by the action of the TET hydroxylase family is important for assisting cells to gain developmental potency, both in vivo and in culture, through the creation of induced pluripotent stem cells (Costa et al., 2014; Hore et al., 2016). Despite this, little is known about the molecular mechanisms that target the TET proteins to their site of action, and currently it is assumed that all sites demethylate with equal efficiency. We report novel cell culture and in vitro demethylation platforms demonstrating that active DNA demethylation proceeds much more rapidly for certain CG containing hexamers compared to others, and that there is logical set of molecular rules governing this preference. These results are significant for understanding epigenetic reprogramming during development, and have implications for synthetic biology and epigenetic editing.