The role of DNA methylation in drug addiction has been increasingly appreciated. Recently, additional forms of DNA epigenetic modifications have been identified through the oxidation of methylated DNA cytosine via TET dioxygenases (TET1, TET2, TET3). However the functional role of TETs in addiction remains largely unknown. We have found that TET1 in the nucleus accumbens (NAc), a key brain reward region, is implicated in cocaine action. In the NAc, there are two major types of medium spiny neurons (MSN), which are classified based on their distinct projections and gene expressions, including enrichment of dopamine D1 and D2 receptors. Though D1- and D2-MSNs are intermingled with similar morphology, they demonstrate different (and often opposite) roles in drug addiction. To identify TET1’s cell type specific functions, we generated the D1- and D2-MSN specific Tet1 knockout mice and characterized their addiction behaviors by using cocaine conditioned place preference and intravenous self-administration. We found that TET1 not only plays opposite roles in D1- and D2-MSNs in cocaine addiction, its effect is also sex-specific. We have been performing whole genome bisulfite sequencing to illustrate TET1 mediated DNA methylation changes in D1- and D2-MSNs. To gain more insight of the DNA epigenetic basis of addiction, we are continuing to explore the role of TET dioxygenases in other aspects of addiction, such as susceptibility difference.