The aim of this review is to evaluate the evidentiary base supporting the hypothesis that the increased hazard for obesity in mood disorder populations (and vice versa) is a consequence of shared pathophysiological pathways. We conducted a PubMed search of all English-language articles with the following search terms: obesity, inflammation, hypothalamic-pituitary-adrenal axis, insulin, cognition, CNS, and neurotransmitters, cross-referenced with major depressive disorder and bipolar disorder. The frequent co-occurrence of mood disorders and obesity may be characterized by interconnected pathophysiology. Both conditions are marked by structural and functional abnormalities in multiple cortical and subcortical brain regions that subserve cognitive and/or affective processing. Abnormalities in several interacting biological networks (e.g. immuno-inflammatory, insulin signaling, and counterregulatory hormones) contribute to the co-occurence of mood disorders and obesity. Unequivocal evidence now indicates that obesity and mood disorders are chronic low-grade pro-inflammatory states that result in a gradual accumulation of allostatic load. Abnormalities in key effector proteins of the pro-inflammatory cascade include, but are not limited to, cytokines/adipokines such as adiponectin, leptin, and resistin as well as tumor necrosis factor alpha and interleukin-6. Taken together, the bidirectional relationship between obesity and mood disorders may represent an exophenotypic manifestation of aberrant neural and inflammatory networks. The clinical implications of these observations are that, practitioners should screen individuals with obesity for the presence of clinically significant depressive symptoms (and vice versa). This clinical recommendation is amplified in individuals presenting with biochemical indicators of insulin resistance and other concurrent conditions associated with abnormal inflammatory signaling (e.g. cardiovascular disease).