Major Depressive Disorder (MDD) is one of the most common and debilitating mental disorders; however, its etiology remains unclear. This paper aims to summarize the major neurobiological underpinnings of depression, synthesizing the findings into a comprehensive integrated view. A literature review was conducted using Pubmed. Search terms included "depression" or "MDD" AND "biology", "neurobiology", "inflammation", "neurogenesis", "monoamine", and "stress". Articles from 1995 to 2016 were reviewed with a focus on the connection between different biological and psychological models. Some possible pathophysiological mechanisms of depression include altered neurotransmission, HPA axis abnormalities involved in chronic stress, inflammation, reduced neuroplasticity, and network dysfunction. All of these proposed mechanisms are integrally related and interact bidirectionally. In addition, psychological factors have been shown to have a direct effect on neurodevelopment, causing a biological predisposition to depression, while biological factors can lead to psychological pathology as well. The authors suggest that while it is possible that there are several different endophenotypes of depression with distinct pathophysiological mechanisms, it may be helpful to think of depression as one united syndrome, in which these mechanisms interact as nodes in a matrix. Depressive disorders are considered in the context of the RDoC paradigm, identifying the pathological mechanisms at every translational level, with a focus on how these mechanisms interact. Finally, future directions of research are identified.