Major depressive disorder is characterized by persistence of sadness, loss of interest or pleasure, feelings of guilt or low self-worth, and other symptoms, including sleep and circadian changes, changes in weight or appetite, and diminished concentration. More than 300 million people worldwide are living with depression, making it the leading global cause of disability.1 Depression can affect people at any age, and can persist or reoccur throughout the lifespan. Previous experience of depression increases the likelihood of future episodes. Women are approximately 50% more likely than men to experience depression, with increased risk associated with puberty, peripartum periods, and menopause. As with other psychiatric disorders, depression is a complex, heterogeneous syndrome. The causes of depression cannot be pinned down to any one biological or external factor, and instead result from the interplay of genetic, neurobiological, environmental, and cultural factors. The genetic heritability of depression is estimated to be from 35%–۴۰%.۲,۳ While heritable genetic factors clearly play a role, a significant proportion of depression risk is attributed to life experience and environment, particularly previous and/or recent stress experience. In the last decade, there has been a considerable focus on the role of epigenetics as a possible bridge between genes and experience in the pathophysiology of depression. The epigenetic landscape, originally envisioned by Waddington more than 60 years ago, sits beautifully at the intersection of genetics, development, environmental influence, and inheritance.4 The word “epigenetic” means “above the genome” and epigenetic mechanisms refer to structural and molecular factors that alter expression of genes without altering the sequence of DNA. These include many types of chemical modifications to histone proteins, DNA, and RNA, as well as alterations in other regulatory proteins and noncoding RNAs.5–۷ While epigenetic mechanisms were previously defined as stable through cell division, the dynamic nature of epigenetic modifications is now understood. As primary regulators of gene expression, epigenetic mechanisms are ideal molecular candidates to flexibly encode and translate environmental factors that increase risk for depression and other highly complex psychiatric syndromes.