Methods for identifying a test agent as a modulator of the active DNA demethylation activity of a DNA methyltransferase are disclosed. The method comprises: a) providing a methylated DNA; b) providing the DNA methyltransferase; c) allowing the methylated DNA to react with the DNA methyltransferase for a sufficient time to perform a demethylation reaction and generate a demethylated DNA product in the presence or absence of a test agent; d) analyzing the extent of demethylation; and d) comparing the extents of the demethylation in the presence and absence of the test agent, and thereby identify the test agent as a modulator of the DNA demethylation activity of the DNA methyltransferase.