Major depressive disorder is a highly prevalent, chronic and recurring disorder, associated with substantial impairment in cognitive and interpersonal functions. Accumulating evidence suggests that inflammatory processes play an important role in the etio-pathogenesis, phenomenology, comorbidity and treatment of MDD. Suboptimal remission rates and the persistence of cognitive deficits contribute to functional impairment in MDD inviting the need for the development of mechanistically novel and domain specific treatment approaches. The MEDLINE/ Pubmed database was searched from inception to February, 9th, 2014 with combinations of the following search terms: ‘TNF-alpha’, ‘depression’, ‘infliximab’, ‘etanercept’, ‘adalimumab’, ‘golimumab’ and ‘certolizumab’. Preclinical and clinical evidence linking TNF-α to MDD pathophysiology were reviewed as well as the current status of TNF-α modulators as novel agents for the treatment of MDD. Experimental models and clinical studies provide encouraging preliminary evidence for the efficacy of TNF- α antagonists in mitigating depressive symptoms and improving cognitive deficits. Further studies are warranted to confirm these data in larger randomized controlled trials in primary psychiatric populations. Translational research provides a promising perspective that may aid the development and/or repurposing of mechanism-based treatments for depressive symptoms and cognitive impairment in MDD.