Bipolar disorder (BD) is associated with high rates of morbidity, comorbidity, disability, economic and human capital costs as well as premature mortality. Although, the past decade has witnessed substantial progress in the treatment of BD, high rates of non-recovery, inter-episodic symptomatology, and episode recurrence remain an ongoing deficiency. Conventional treatments for BD are capable of alleviating 'surface-based' symptomatology yet no agent is disease-modifying. Translational research initiatives provide evidence that mood disorder symptomatology is subserved by disturbances in interacting immuno-inflammatory, metabolic, and neuroendocrine networks. Numerous studies document elevated pro-inflammatory circulating cytokines [e.g. interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)], in individuals with BD as compared to healthy volunteers. Elevated peripheral levels of TNF-alpha and its receptors (i.e. TNF-R1 and TNF-R2) are a frequent findings across depressive and manic states and may persist into euthymia. As such, TNF-alpha may constitute a trait marker of BD. Other markers of inflammation including acute phase reactants (e.g. C-reactive protein) and vascular adhesion molecules (e.g. intercellular adhesion molecule-1) are also altered in BD. Herein, we review supporting evidence for the hypothesis that disturbances in inflammatory homeostasis, as marked by elevated TNF-alpha levels, are salient to the pathophysiology of BD and provide a platform for novel drug discovery. In this review, we propose that TNF-alpha modulation is a target for disease-modifying treatment of BD. To support this hypothesis, we review evidence from clinical trials evaluating the efficacy of TNF-alpha antagonists (i.e. adalimumab, etanercept, and infliximab) on depressive symptoms and mental health-associated quality of life measures.