The article explores the role of inflammation in the development of depression and its potential as a therapeutic target. It begins by discussing the evolutionary perspective, suggesting that early humans evolved to respond to pathogens and predators with inflammatory responses, which may have provided an advantage. However, in modern times, these same inflammatory responses can contribute to the development of depression and non-responsiveness to conventional antidepressants. The authors review recent data on how the immune system interacts with neurotransmitters and neurocircuits to influence depression risk. They highlight the involvement of inflammasomes, which are key immunological interfaces between stress and inflammation, and the cellular pathway of immune cell trafficking to the brain. The article also examines the impact of inflammation on neurotransmitter systems, particularly serotonin, noradrenaline, dopamine, and glutamate, and how it affects neurocircuitry related to motivation, motor activity, and anxiety. Additionally, it discusses the role of T cells in resilience to depression and the potential of anti-inflammatory treatments, noting that they may be most effective in subgroups of patients with increased peripheral inflammation. The authors conclude by emphasizing the need for further research to understand the inflammatory mechanisms in depression and to develop novel therapeutic approaches.The article explores the role of inflammation in the development of depression and its potential as a therapeutic target. It begins by discussing the evolutionary perspective, suggesting that early humans evolved to respond to pathogens and predators with inflammatory responses, which may have provided an advantage. However, in modern times, these same inflammatory responses can contribute to the development of depression and non-responsiveness to conventional antidepressants. The authors review recent data on how the immune system interacts with neurotransmitters and neurocircuits to influence depression risk. They highlight the involvement of inflammasomes, which are key immunological interfaces between stress and inflammation, and the cellular pathway of immune cell trafficking to the brain. The article also examines the impact of inflammation on neurotransmitter systems, particularly serotonin, noradrenaline, dopamine, and glutamate, and how it affects neurocircuitry related to motivation, motor activity, and anxiety. Additionally, it discusses the role of T cells in resilience to depression and the potential of anti-inflammatory treatments, noting that they may be most effective in subgroups of patients with increased peripheral inflammation. The authors conclude by emphasizing the need for further research to understand the inflammatory mechanisms in depression and to develop novel therapeutic approaches.