Substance use disorder is a chronic condition of compulsive drug seeking and use that is mediated by stable changes in central reward pathways. Repeated use of abused drugs causes persistent alterations in gene expression responsible for the long-term behavioral and structural changes. Recently, it has been suggested that epigenetic mechanisms are responsible in part for these drug-induced changes in gene expression. One of the alluring aspects of epigenetic regulation of gene expression is that epigenetic mechanisms may provide transient and potentially stable conditions that in turn may ultimately participate in the molecular mechanisms required for neuronal changes subserving long-lasting changes in behavior. This review describes epigenetic mechanisms of gene regulation and then discusses the emerging role of epigenetics in drug-induced plasticity and behavior. Understanding these mechanisms that establish and maintain drug-dependent plasticity changes may lead to deeper understanding of substance use disorders as well as novel approaches to treatment.