Focusing on drug addiction and depression, this chapter discusses the molecular machinery underlying epigenetic mechanisms and describes how their dysregulation may contribute to the chronic psychiatric disorders. While the epigenetic studies are ongoing for a variety of substance abuse models, the chapter focuses on the psychostimulants cocaine and amphetamine because these studies are more mature. One of the most challenging obstacles for depression research has been the development of an animal model that accurately recapitulates the symptoms of human depression. Brain-derived neurotrophic factor (BDNF) plays a critical role in the development of the social defeat phenotype and its reversal by antidepressant treatment. While extremely exciting, epigenetic research in psychiatry is still in its infancy, and far more research is needed to identify both the dysregulated genes and chromatin modifications responsible for individual psychiatric diseases and their improvement during effective therapy.