This review provides an overview of the neurocircuitry underlying mood disorders, focusing on the limbic system and its connections to the prefrontal cortex. The limbic system, including the amygdala, hippocampus, and other structures, has been identified as central to emotional processing. Detailed anatomical data from the 1970s and 1980s revealed specific circuits linking the medial prefrontal cortex, amygdala, ventral striatum, pallidum, medial thalamus, hypothalamus, and periaqueductal gray. These circuits are crucial for mood disorders, as evidenced by functional and structural imaging studies in humans. The review highlights the historical development of understanding the limbic system, from early observations in the 1930s to more recent neuroanatomical studies in non-human primates. Key findings include the role of the amygdala in emotional responses and the involvement of the medial prefrontal cortex in mood regulation. The review also discusses the clinical implications of these findings, such as the somatic marker hypothesis, which suggests that visceral reactions guide behavior. Recent neuroimaging studies in humans with mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), have shown alterations in gray matter volume, cellular elements, neurophysiological activity, receptor pharmacology, and gene expression in the medial prefrontal network and related limbic structures. These abnormalities are associated with disturbances in emotional behavior, cognitive functions, and autonomic and neuroendocrine functions. The review concludes by discussing the potential therapeutic targets within these circuits, such as the subgenual anterior cingulate cortex (sgACC), ventromedial frontal polar cortex, ventromedial striatum, and amygdala, which have been targeted in treatments for depression.This review provides an overview of the neurocircuitry underlying mood disorders, focusing on the limbic system and its connections to the prefrontal cortex. The limbic system, including the amygdala, hippocampus, and other structures, has been identified as central to emotional processing. Detailed anatomical data from the 1970s and 1980s revealed specific circuits linking the medial prefrontal cortex, amygdala, ventral striatum, pallidum, medial thalamus, hypothalamus, and periaqueductal gray. These circuits are crucial for mood disorders, as evidenced by functional and structural imaging studies in humans. The review highlights the historical development of understanding the limbic system, from early observations in the 1930s to more recent neuroanatomical studies in non-human primates. Key findings include the role of the amygdala in emotional responses and the involvement of the medial prefrontal cortex in mood regulation. The review also discusses the clinical implications of these findings, such as the somatic marker hypothesis, which suggests that visceral reactions guide behavior. Recent neuroimaging studies in humans with mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), have shown alterations in gray matter volume, cellular elements, neurophysiological activity, receptor pharmacology, and gene expression in the medial prefrontal network and related limbic structures. These abnormalities are associated with disturbances in emotional behavior, cognitive functions, and autonomic and neuroendocrine functions. The review concludes by discussing the potential therapeutic targets within these circuits, such as the subgenual anterior cingulate cortex (sgACC), ventromedial frontal polar cortex, ventromedial striatum, and amygdala, which have been targeted in treatments for depression.