The article provides a comprehensive overview of the molecular neurobiology of depression, highlighting the challenges in understanding its pathophysiology due to the heterogeneity of depressive syndromes and the difficulty in reproducing certain symptoms in animal models. Recent studies combining behavioral, molecular, and electrophysiological techniques have revealed that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. The article also discusses the role of monoamines, neurotrophins, neuroendocrine and neuroimmune interactions, and epigenetic mechanisms in the pathophysiology of depression. Additionally, it explores new insights and therapeutic approaches, such as the rapid antidepressant effects of ketamine and the potential of viral-mediated gene delivery. The authors emphasize the need for a multidisciplinary approach to understand the neurobiological bases of depression and improve treatment outcomes.The article provides a comprehensive overview of the molecular neurobiology of depression, highlighting the challenges in understanding its pathophysiology due to the heterogeneity of depressive syndromes and the difficulty in reproducing certain symptoms in animal models. Recent studies combining behavioral, molecular, and electrophysiological techniques have revealed that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. The article also discusses the role of monoamines, neurotrophins, neuroendocrine and neuroimmune interactions, and epigenetic mechanisms in the pathophysiology of depression. Additionally, it explores new insights and therapeutic approaches, such as the rapid antidepressant effects of ketamine and the potential of viral-mediated gene delivery. The authors emphasize the need for a multidisciplinary approach to understand the neurobiological bases of depression and improve treatment outcomes.