Although evidence suggests that chronic elevations in immune-inflammatory signaling can precipitate mood symptoms in a subset of individuals, associated risk and resilience mechanisms remain poorly understood. Long-chain omega-3 (LCn-3) fatty acids, including eicosapentaenic acid (EPA) and docosahexaenoic acid (DHA), have anti-inflammatory and inflammation-resolving properties that maintain immune-inflammatory signaling homeostasis. Cross-sectional evidence suggests that the mood disorders major depressive disorder and bipolar disorder are associated with low EPA and/or DHA biostatus, elevations in the LCn-6:LCn-3 fatty acid ratio, and elevated levels of pro-inflammatory eicosanoids, cytokines, and acute-phase proteins. Medications that are effective for reducing depressive symptoms or stabilizing manic depressive oscillations may act in part by downregulating immune-inflammatory signaling and are augmented by anti-inflammatory medications. Recent prospective longitudinal evidence suggests that elevations in the LCn-6:LCn-3 fatty acid ratio are a modifiable risk factor for the development of mood symptoms, including depression and irritability, in response to immune-inflammatory signaling. Together these data suggest that increasing LCn-3 fatty acid intake and biostatus represents a feasible strategy to mitigate the negative impact of elevated immune-inflammatory signaling on mood stability. Key teaching points: • Long-chain omega-3 (LCn-3) fatty acids have anti-inflammatory and inflammation-resolving properties. • Major mood disorders are associated with both LCn-3 fatty acids deficiency and elevated immune-inflammatory signaling. • Prospective evidence suggests that low LCn-3 fatty acid biostatus increases risk for developing inflammation-induced mood dysregulation. • Taken collectively, this evidence suggests that increasing LCn-3 fatty acid intake and biostatus represents a promising strategy to mitigate the detrimental effects of elevated immune-inflammatory signaling on mood.