There is very little empirical work that directly assesses the neurobiological association of personality superfactors with the liability to depression. Therefore, as a means of providing a framework for future research, this article outlines the putative neurobiological foundation of three major personality superfactors: positive emotionality or extraversion, constraint or psychoticism, and negative emotionality or neuroticism. The neurobiology of these superfactors, particularly the central dopamine, serotonin, and norepinephrine projection systems, respectively, is derived largely from animal biobehavioral research, although human work is discussed where available. In an attempt to explore the association of this framework to depression, extreme quantitative variation in the resulting neurobiological systems, alone and in interaction with each other, is discussed in terms of different forms of depression and of modification of the phenotype and course of depression. The effects of experience on neurobiological functioning is briefly considered as a therapeutic approach, in lieu of, or in interaction with, pharmacological modulation of behavior.