Mounting evidence from clinical and preclinical studies incriminates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of proinflammatory cytokines have been repeatedly demonstrated in both major depressive disorder and bipolar disorder. Moreover, the induction of a proinflammatory state, for example by injecting lipopolysacchride in healthy subjects induces “sickness behavior”, resembling depressive symptomatology. Potential mechanisms include pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes. Neuroinflammation is a condition in which brain tissue is effected by a chronic, low-grade inflammation. While cytokines are the chief mediators, ensuing changes in tryptophan metabolism and increased oxidative stress start a vicious cycle, resulting in apoptosis of neurons in crucial mood regulating areas of the brain. Newer psychopharmacological drugs appear to decrease the neuroinflammatory process, and efficacious treatments are associated with a reduction in inflammatory markers, both peripherally and centrally. Further, anti-inflammatory agents such as acetyl-salicylic acid, celecoxib, anti-TNF-α therapies, minocycline, curcumin and omega-3 fatty acids are being re-purposed for use in mood disorders. While there is selected evidence of efficacy for these agents in an adjunctive role, further research is necessary to establish their therapeutic benefit. There is a great need for novel medications which aim at the biological pathways that lead to the development of mood disorders, and targeting inflammation is an important strategy in ameliorating these conditions, as well as the accompanying comorbidities.