Background: While downregulation of several growth factors in major depressive disorder is well established, less attention has been paid to the upregulation of other growth factors. Yet, upregulated growth factors may offer better therapeutic targets. We show that connective tissue growth factor (CTGF) represents a target based on its upregulation in major depressive disorder and studies in animal models implicating it in negative affect. Methods: CTGF gene expression was first evaluated in the postmortem human amygdala. The findings were followed up in outbred rats and in two rat lines that were selectively bred for differences in novelty-seeking and anxiety behavior (bred low responders and bred high responders). We studied the impact of social defeat and early-life treatment with fibroblast growth factor 2 on CTGF expression. Finally, we assessed the ability of an anti-CTGF antibody (FG-3019) to alter CTGF expression and emotionality. Results: In the human amygdala, CTGF expression was significantly increased in major depressive disorder compared with control subjects. CTGF expression was also significantly increased in the dentate gyrus of adult bred low responders compared with bred high responders. Social defeat stress in bred low responders significantly increased CTGF expression in the dentate gyrus. Early-life fibroblast growth factor 2, a treatment that reduces anxiety-like behavior throughout life, decreased CTGF expression in the adult dentate gyrus. In outbred rats, CTGF administration increased depression-like behavior. Chronic treatment with FG-3019 decreased CTGF expression, and acute and chronic treatment was antidepressant. Conclusions: This study is the first to implicate CTGF as a prodepressant molecule that could serve as a target for the development of novel therapeutics.