The heritability of major depression has been documented in a number of epidemiologic studies. Twin studies have estimated the heritability at about 37% and these estimation can rise up to 70% if severity, relapse rate and age of onset are considered. Despite the relative importance of genetic risk factors in the pathogenesis of this disease, molecular genetic studies, including large genome-wide association studies, only a very small number of candidate genes, explaining little of the variance have been identified. This fact has been termed "missing heritability" and could be accounted by a number of factors including that the presumed causal variants are not tagged by the current genetic approaches, that major depression is truly polygenic, with each polymorphism only contributing very small increases in risk, unaccounted environmental influences and complex epigenetic factors. Epigenetics refers to the regulation of DNA transcription without alteration of the original sequence and is controlled by DNA methylation, histone modifications and non-coding RNAs and can be transmitted through generations. A number of clinical and preclinical studies suggest that epigenetic mechanisms could play an important role in the pathogenesis and treatment of major depression. So far, most studies investigated genes within the hypothalamicpituitary- adrenal (HPA) axis or the neurotrophin system. It is also of interest that current psychopharmacologic drugs including antidepressants, antipsychotics and mood stabilizers may exert some of their effects by inducing epigenetic changes. Most notably, epigenetic alterations are potentially reversible and accessibe for drug treatment, which lead to the development of novel classes of antidepressant drugs.