Growing evidence supports the hypothesis that epigenetics is a key mechanism through which environmental exposures interact with an individual’s genetic constitution to determine risk for depression throughout life. Epigenetics, in its broadest meaning, refers to stable changes in gene expression that are mediated via altered chromatin structure without modification of DNA sequence. According to this hypothesis, severe stress triggers changes—in vulnerable individuals—in chromatin structure at particular genomic loci in the brain’s limbic regions, which drive sustained changes in gene expression that contribute to episodes of depression.