The serotonin transporter gene has been hypothesized to influence, possibly in interaction with environmental factors, the vulnerability for depression. So far, genetic studies have tested the association of the repeat polymorphism (5-HTTLPR) with depression and whether it is moderated by exposure to stressful events. This has not yielded unequivocal results, even across meta-analyses. However, environmental factors may induce epigenetic changes in the structure of DNA that can influence gene expression. These epigenetic effects may be independent of the genetic polymorphisms in the gene region. This editorial reviews an article in this issue that compared the intrapair differences in depressive symptoms in monozygotic twin pairs with the intrapair differences of methylation at cytosine-guanine dinucleotide sites in the promoter region of the serotonin transporter gene. Differences in depressive symptoms were correlated with differences in methylation status, such that higher methylation, which, in this sample of identical twins, must be environmental in origin, is associated with more depressive symptoms. Noteworthy is the fact that the epigenetic effects were independent of the 5-HTTLPR. These results should encourage genome-wide testing of the contribution of epigenetic effects to depression.