In this issue of Science Translational Medicine, Alexander and colleagues describe coherent evidence drawn from humans and from modeled animals that supports a brain region-specific gene therapy for depression: adeno-associated virus (AAV)-mediated transfer of the gene encoding p11 to the nucleus accumbens (NAcc). The investigators found that focal NAcc knockdown of p11 expression in mice resulted in behavioral deficits related to depression and that AAV-mediated p11 gene transfer to the NAcc rescued the depression-related behavioral deficits of mice in which endogenous p11 had been genetically knocked out. They also found that p11 levels were lower in the NAcc of patients with depression than in the NAcc of matched controls. Taken together, the data suggest that gene therapies aimed at enhancing p11 in the NAcc may represent promising new approaches for treating depression; however, a large number of clinical and regulatory issues must be overcome before such therapies can be implemented.