Based on earlier gene expression and chromatin array data, we identified the protein, dishevelled-2 (DVL2), as being regulated in the nucleus accumbens (NAc), a key brain reward region, in the mouse social defeat model of depression. Here, we validate these findings by showing that DVL2 mRNA and protein levels are downregulated in NAc of mice susceptible to social defeat stress, effects not seen in resilient mice. Other DVL isoforms, DVL1 and DVL3, show similar patterns of regulation. Downregulation of DVL was also demonstrated in the NAc of depressed humans examined postmortem. Interestingly, several members of the WNT (Wingless)-DVL signaling cascade, including phospho-GSK3β (glycogen synthase kinase-3β), also show significant downregulation in the NAc of susceptible, but not resilient, mice, demonstrating concerted regulation of this pathway in the NAc due to social defeat stress. By using viral-mediated gene transfer to overexpress a dominant negative mutant of DVL in NAc, or by using of a pharmacological inhibitor of DVL administered into this brain region, we show that blockade of DVL function renders mice more susceptible to social defeat stress and promotes depression-like behavior in other assays. Similar pro-depression-like effects were induced upon overexpressing GSK3β in the NAc, while overexpressing a dominant negative mutant of GSK3β promoted resilience to social defeat stress. These findings are consistent with the knowledge that downregulation of DVL and of phospho-GSK3β reflects an increase in GSK3β activity. These studies reveal a novel role for the DVL-GSK3β signaling pathway, acting within the brain’s reward circuitry, in regulating susceptibility to chronic stress.