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The increasing global burden calls for the development of novel approaches to tackle unmet needs in prevention and treatment of depression underlying biological, psychological and social dysregulations. Depressed patients with chronic low-grade inflammation might be classified as a subgroup of major depressive disorder (MDD); therefore, looking for antidepressant therapies from anti-inflammatory pathways could improve treatment effectiveness for this subgroup of patients. Omega-3 (or n-3) polyunsaturated fatty acids (PUFAs) are anti-inflammatory both in peripheral organs and central nervous systems and have clinically applied in the treatment and prevention of depression, cardiovascular diseases, dyslipidaemia, diabetes and arthritis. Anthropological studies suggest that human beings evolved to a modern diet with less than one-tenth of omega-3 to omega-6 PUFAs intake ratio, which leads to a constitutional bias toward chronic systemic inflammatory status to explain dramatically increasing of depression and chronic medical illnesses in modern world. The presentation is to provide our recent clinical and pre-clinical studies and an overview about the role of inflammation in “mind-body” comorbidity and present anti-inflammatory mechanisms by which n-3 PUFAs may orchestrate the molecular and cellular functions and facilitate the therapeutic pathways in chronic medical illnesses and depression.