Throughout his life and his work, Cajal realized the potential of the neurons he was so carefully studying and how, grouped in systems, they served the special senses and the maintenance and proper functioning of the organism. Over the past 25 years, major depression and suicide have come to be recognized as associated with alteration in serotonergic neurons and their target receptors. We examined whether prefrontal cortical (PFC) serotonin transporter sites (SERT) differ in major depression and suicide by quantitative receptor autoradiography. Clinical information was obtained by psychological autopsy. We found regionally distinct neurobiological correlates of major depression and suicide. A diffuse reduction of SERT binding throughout the dorsoventral extent of the PFC in major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathology in major depression. The localized reduction in SERT binding in ventral PFC found in suicide victims may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. It is conceivable that Cajal envisioned that psychiatric illness would be the result of "psychic neuron" pathophysiology. Today's informed psychiatrists will not be able to deny the role of the brain in the mental ailments that afflict their patients.