The article reviews the role of inflammatory cytokines in the development of depression, both in medically ill and healthy individuals. It highlights the neurobiological mechanisms by which cytokines can influence neurocircuitry and neurotransmitter systems, leading to behavioral alterations. The review discusses how chronic exposure to elevated inflammatory cytokines can cause neuropsychiatric disorders and depression, involving the activation of inflammatory signaling pathways that affect monoamine, glutamate, and neuropeptide systems, as well as growth factors like brain-derived neurotrophic factor (BDNF). The article also explores the potential genetic and environmental factors that mediate the development of cytokine-related depression, including childhood trauma, obesity, stress, and poor sleep. Additionally, it examines the therapeutic implications, suggesting that targeting inflammatory cytokine signaling or its consequences on neurotransmitter systems could be a novel approach to prevent or reverse cytokine-induced behavioral changes. The review concludes by discussing specific gene polymorphisms and neurotransmitter systems that may confer protection or vulnerability to symptom dimensions of cytokine-related depression.The article reviews the role of inflammatory cytokines in the development of depression, both in medically ill and healthy individuals. It highlights the neurobiological mechanisms by which cytokines can influence neurocircuitry and neurotransmitter systems, leading to behavioral alterations. The review discusses how chronic exposure to elevated inflammatory cytokines can cause neuropsychiatric disorders and depression, involving the activation of inflammatory signaling pathways that affect monoamine, glutamate, and neuropeptide systems, as well as growth factors like brain-derived neurotrophic factor (BDNF). The article also explores the potential genetic and environmental factors that mediate the development of cytokine-related depression, including childhood trauma, obesity, stress, and poor sleep. Additionally, it examines the therapeutic implications, suggesting that targeting inflammatory cytokine signaling or its consequences on neurotransmitter systems could be a novel approach to prevent or reverse cytokine-induced behavioral changes. The review concludes by discussing specific gene polymorphisms and neurotransmitter systems that may confer protection or vulnerability to symptom dimensions of cytokine-related depression.