Monoamine based treatments of depression are only effective in a select population of patients. Under-standing the pathogenesis and mechanisms of depression may offer novel therapies where typical mon-oamine treatments fail. We present evidence for the role of low-grade systemic activation of the innate immune system in the pathogenesis of depression, antidepressant response, anti-inflammatory treat¬ment of depression, and physical comorbidities of depression. Cross-sectional studies have demonstrated a relationship between specific inflammatory blood biomarkers (IL-6, CRP and TNF-alpha) and depression. Longitudinal studies show inflammation is not an epiphenomenon of depression: inflammatory biomarkers precede depressive symptoms. Evidence from animal studies have detailed mechanisms whereby peripheral inflammatory signals are communicated to the brain, affecting mood, cognition and behaviour. Pharmacologically, a high IL-6 level predicts poor response to selective serotonin reuptake inhibitors and it remains elevated in non-responders, indicating inflammatory cytokines may underlie treatment-resistance. Furthermore, anti-cytokine treatments have substantial anti-depressant effects comparable to conventional antidepressant medication, at least in patients with co-morbid depression and high levels of peripheral inflammation. There is also evidence that inflammation links depression and physical illness, with elevated inflammatory markers mediating the relationship between depression and both childhood maltreatment and coronary heart disease. Clearly, the role of inflammation in depression is complex. To understand the relationship better, studies need to examine causality of the association and the efficacy of novel immunotherapies in depressed patients without chronic physical illness.