Low-grade systemic inflammation and neuroinflammation are implicated in the development and maintenance of some cases of depression. This chapter explores the evolutionary psychoneuroimmunological pathways characterizing the inflammatory pathogenesis of depression. The strongest evidence for the link between inflammation and major depressive disorder comes from studies in humans and other animals that have found that the activation of the immune system by immune challenges or by the administration of proinflammatory cytokines induces symptoms of depression in individuals without any previous mental disorders. An estimated 34% of the adult US population have low-grade systemic inflammation. As many as 27% of depressed patients may be affected by neuroinflammation. Low-grade systemic inflammation and neuroinflammation appear to be evolutionarily novel and likely maladaptive pathophysiological outcomes caused by contemporary western lifestyles – most notably by such factors as contemporary western diets, obesity, visceral fat, gut dysbiosis, and chronic stress. Inflammatory states may cause symptoms of depression because the increase of proinflammatory cytokines can lead to the body reacting to it as it does with infection: to produce sickness behaviors that help save energy so that the immune system can overcome the infection, which in this case is not an infection but a more chronic lifestyle-driven inflammatory state.