Epigenetic modifications of chromatin, including the genomic DNA and histone proteins, play critical roles in orchestrating transcriptomes of all cell types. We found that neuronal stimulation induces region-specific active DNA demethylation in a Gadd45b- and TET1-dependent fashion in the adult mouse dentate granule neurons in vivo (Ma et al. Science 2009; Guo et al. Cell 2011). Our genome-wide analysis further revealed that 1.4% of all CpGs measured exhibit rapid activity-induced demethylation or de novo methylation (Guo et al. Nat. Neurosci. 2011). These activity-modified CpGs exhibit a broad genomic distribution with significant enrichment in low-CpG density regions, and are associated with brain-specific genes related to neuronal plasticity. Our single-base methylome analysis discovered significant levels of nonCpG methylation in these neurons and we identified DNMT3A and MeCP2 as a writer and a reader for nonCpG DNA modification (Guo et al. Nat. Neurosci. 2013). More recently, our studies suggest that active DNA demethylation and DNA repair serve as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons and animal behavior (Yu et al. Nat. Neurosci. 2015). Together, our studies implicate novel modifications of the neuronal DNA methylome as a previously under-appreciated mechanism for activity-dependent epigenetic regulation in the adult nervous system under both physiological and pathological conditions.