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Our basic thesis is that depression is an evolutionarily conserved mechanism in mammalian brains, selected as a shutdown mechanism to terminate protracted separation distress (a prototype mammalian emotional state), which, if sustained, would be dangerous for infant mammals. However, this fundamental shutdown mechanism remains available to more mature mammalian and hominid brains, particularly those with certain polymorphisms in genetic endowment, early loss/separation trauma, or other predisposing factors, which can promote reactivation in relationship to almost any chronic stressor. Such evolutionarily selected shutdown mechanisms could become hypertrophied, and released from normal adaptive control mechanisms in vulnerable individuals, to potentially yield the full spectrum of depressive illness. Depression remains a challenging puzzle of neurobiological correlates, involving changes in many biogenic amine and neuropeptide systems and alterations in neuroendocrine and immune function. We suggest that core factors form an interactive and even synergistic “depressive matrix,” which argues against any “single-factor” theory. We examine core contributions from stress cascades, immune function, and multiple neuropeptide and monoamine systems. Contrary to many single-factor or primary factors, our review suggests active synergisms between factors, as well as a complex recursive (looping) control architecture regulating both entry and exit from depression. Such an interactive matrix of factors may help explain why such an enormous multiplicity of potential treatments are antidepressant, ranging from psychotherapy and exercise to multiple drugs, vagal and deep brain stimulation, and ECT. This review bridges domains generally disconnected in current literature. Traditional biological psychiatric perspectives are almost totally “bottom-up” (neglecting relationships between depression and social stress) and typically cannot explain why depression is such a pervasive problem, or why evolution could have ever selected for such a mechanism. Linking depression to protracted separation distress provides a heuristic potential integration of findings, particularly between long-standing psychotherapy and psychodynamic perspectives and emerging neuroscience insights. This hypothesis yields various testable predictions at both clinical and neuroscience levels.