Like all psychiatric conditions, depression is a complex phenomenon that is unlikely to yield to simple monolithic explanatory paradigms. Nonetheless, increasing evidence suggests that the immune system in general and inflammatory processes in particular, may contribute to depressive pathogenesis in a significant proportion of otherwise medically healthy individuals struggling with the disorder. In this chapter, we review the best current evidence suggesting that inflammatory processes contribute to the development of depression, both via direct actions on the brain as well as by effects on secondary pathways that marry brain to body. We review epidemiological evidence linking inflammation to depression before reviewing findings that exposure to inflammatory stimuli produce depressive symptoms in concert with brain-body changes known to be common in depression. Following this review of the role of inflammation in depressive causation, we consider emerging evidence that immunomodulatory interventions may hold promise as antidepressants, especially in individuals with elevations in peripheral inflammatory biomarkers. Interventions discussed include cytokine and cyclo-oxygenase antagonists, as well as agents that impact inflammatory transcription factors/signaling cascades. We conclude with a brief discussion of the potential role of various behavioral strategies in reducing inflammation and thereby enhancing emotional well-being.