The article reviews the neuroimmune network model of depression, emphasizing its bidirectional communication between the brain and the immune system. It highlights how cellular actors and signaling molecules can modulate brain structure and function, particularly in the cortico-amygdala circuit, cortico-striatal circuit, and prefrontal cortex. Dysregulated inflammation, especially under chronic stress, can lead to dysphoria, distress, and anhedonia, initiating self-medicating behaviors that further heighten inflammation. This dysregulation forms a positive feedback loop, increasing the risk for depression, especially during adolescence. The authors extend this model to a developmental framework, examining comorbidity with other psychiatric disorders and stress-related medical illnesses. They also discuss the potential for interventions targeting neuroimmune signaling to treat and prevent depression in youth and adolescents. The article underscores the importance of early-life adversity and its impact on immune function, which can exacerbate stress during adolescence, making it a critical period for the onset of depression.The article reviews the neuroimmune network model of depression, emphasizing its bidirectional communication between the brain and the immune system. It highlights how cellular actors and signaling molecules can modulate brain structure and function, particularly in the cortico-amygdala circuit, cortico-striatal circuit, and prefrontal cortex. Dysregulated inflammation, especially under chronic stress, can lead to dysphoria, distress, and anhedonia, initiating self-medicating behaviors that further heighten inflammation. This dysregulation forms a positive feedback loop, increasing the risk for depression, especially during adolescence. The authors extend this model to a developmental framework, examining comorbidity with other psychiatric disorders and stress-related medical illnesses. They also discuss the potential for interventions targeting neuroimmune signaling to treat and prevent depression in youth and adolescents. The article underscores the importance of early-life adversity and its impact on immune function, which can exacerbate stress during adolescence, making it a critical period for the onset of depression.