The article reviews the growing body of evidence suggesting that inflammatory responses play a significant role in the pathophysiology of depression. It highlights that depressed patients exhibit elevated levels of proinflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules. The therapeutic administration of interferon-α, a potent inducer of proinflammatory cytokines, can lead to depression in up to 50% of patients. Proinflammatory cytokines interact with various pathophysiological domains associated with depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and behavior. Stress, which can trigger depression, also promotes inflammatory responses through effects on the sympathetic and parasympathetic nervous systems. The article suggests that depression may be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation. These findings indicate that targeting proinflammatory cytokines and their signaling pathways could represent a novel strategy for treating depression. The article also discusses the evolutionary perspective on the link between depression and inflammation, suggesting that the high prevalence of mood disorders may be due to the pleiotropic effects of genes that promote enhanced inflammatory responses, which were advantageous in ancestral environments but may now pose risks in modern settings.The article reviews the growing body of evidence suggesting that inflammatory responses play a significant role in the pathophysiology of depression. It highlights that depressed patients exhibit elevated levels of proinflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules. The therapeutic administration of interferon-α, a potent inducer of proinflammatory cytokines, can lead to depression in up to 50% of patients. Proinflammatory cytokines interact with various pathophysiological domains associated with depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and behavior. Stress, which can trigger depression, also promotes inflammatory responses through effects on the sympathetic and parasympathetic nervous systems. The article suggests that depression may be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation. These findings indicate that targeting proinflammatory cytokines and their signaling pathways could represent a novel strategy for treating depression. The article also discusses the evolutionary perspective on the link between depression and inflammation, suggesting that the high prevalence of mood disorders may be due to the pleiotropic effects of genes that promote enhanced inflammatory responses, which were advantageous in ancestral environments but may now pose risks in modern settings.