Recent research has shed light on the intricate relationship between mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), and inflammation. This chapter explores the complex interplay involving immune and metabolic dysfunction in the pathophysiology of these disorders, emphasizing their association with autoimmunity/inflammatory conditions, chronic low-grade systemic inflammation, T cell overactivation, and immunosenescence. This perspective underscores the notion that MDD and BD are not solely brain disorders, highlighting their nature as multi-system conditions.