Epigenetic modifications can alter gene expression through mechanisms that are heritable, but do not involve direct changes in the nucleotide sequence of the genome. Recent findings have suggested that epigenetic modifications are associated with several psychiatric disorders. As such, this chapter will introduce the general principles of epigenetics and molecular mechanisms, and discuss the implications they have on major depressive disorder. We first begin with DNA methylation, as it is the most widely studied epigenetic modification. The importance of DNA methylation is outlined by monozygotic twin studies of major depressive disorder, and the role it plays in each of the three theories of depression. Afterward, we present two additional epigenetic modifications-histone modifications and noncoding RNAs-and their role in depression. In each section, we will also briefly touch on the therapeutic impact on patient diagnosis and care.