Major depressive disorder (MDD) is notoriously difficult to treat in the long term. In mice subjected to chronic social defeat stress (a preclinical model of depression-like behaviours), the authors found both reduced Rac1 transcription in the nucleus accumbens (NAc) and depression-like behaviour, which were rescued by pharmacological inhibition of class I histone deacetylases. Similar molecular changes were observed in the NAc of depressive subjects. Furthermore, RAC1 overexpression prevented the stubby spines observed in the NAc of mice subjected to social defeat stress and the depression-related behaviours. These findings suggest that epigenetic regulation of RAC1 in the NAc could be involved in MDD.