Unipolar depression, also known as Major Depressive Disorder (MDD), is a condition that has a profound effect on the everyday functioning of an individual, going beyond just mood changes. Recent studies have emphasized the importance of a number of structural, physiological, neurochemical, neuroendocrine, and inflammatory problems in the nervous system in the exacerbation of cognitive, emotional, and social interaction problems in MDD. It is important to note that problems related to attention, memory, executive function, and motivation are linked to structural problems in the most important regions of the brain, such as the prefrontal cortex, hippocampus, and anterior cingulate cortex. Moreover, problems with the functioning of the brain networks, such as the default mode, central executive, and salience networks, are also common. Neuroinflammation further adds to the problems associated with MDD, as it is also responsible for problems such as fatigue, psychomotor slowing, and social isolation. In addition, neurotransmitter dysregulation and hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis worsen the functional detriments in those with MDD. This chapter interprets the pathophysiology of unipolar depression at a neurobiological level in reference to the knowledge we have gained using state-of-the-art neuroscience today. It emphasizes the significance of these networks for the development of targeted treatment interventions e.g. (cognitive) remediation, transcranial magnetic stimulation, psychotherapy, and medication. A comprehensive understanding of various neurobiological perspectives would be critical to developing individualized treatment strategies that are specifically tailored for the prevention of disability and restoration of functioning in MDD patients.