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The separation distress hypothesis of depression, formulated in 2009, offered an affective neuroscience perspective on our most common and costly mental health condition, as an alternative to molecular reductionism in psychiatry. Our hypothesis constituted a neurobiological extension of classic work on depression as intrinsically related to attachment and loss, integrating psychological and neurobiological findings from clinical and preclinical models. We posited three ideas: 1) depression is an evolutionarily conserved vulnerability within the social-affective endowment of mammalian brains, involving interactions between separation distress and other conserved CNS systems; 2) this mechanism adaptively shuts down protracted separation distress, potentially lethal to infant mammals, and thus protective in a circumscribed form, explaining its conservation; 3) this process has no single biological ‘lever’ and is instantiated through complex recursion. Like other conserved processes, it overlaps with kindred processes also serving behavioral shutdown, particularly hibernation and sickness behavior. Epicenters for depression include a large array of systems regulating the CNS and its behavioral/affective states: the stress axis, immune systems, monoamine and cholinergic systems, GABA and glutamate systems, and large molecule pro-social neuropeptide systems, all dynamically linked. This review tracks multiple developments in the last 10 years including growing public health and healthcare awareness about the biological and not just psychological impact of our primary relationships, and its corollary, the neurobiologically destructive effects of trauma, abuse, neglect, and social isolation. Secure attachment is both a psychological and biological necessity, and its loss or traumatic disruption may constitute a fertile ground for depression in all its forms.