The burden of depression as a severe illness with high suicidality and prevalence is immense. Despite substantial advancement in psychopharmacology and psychotherapy over the last decades a residual group of very ill patients with a chronic disease and high suicidal risk remains. Modern theories about the pathophysiology of depression are derived from studies examining the mechanism of antidepressants influencing the serotonergic (5-HT) and noradrenergic (NE) systems. Serotonergic fibers originate from the dorsal raphe nuclei (DRN), noradrenergic fibers from the locus coeruleus (LC). Both nuclei represent relatively small brain regions and both are controlled to some extent by the habenular complex. We propose the hypothesis of an overactivation of the habenula in human major depressive episodes (MDE's). Increased activation of the lateral habenular nucleus leads to the down regulation of the serotonergic, noradrenergic, dopaminergic systems and stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Functional inhibition of the lateral habenula via deep brain stimulation (DBS) has antidepressive properties. The hypothesis is based on the findings of a clinical imaging study examining the habenular after tryptophan depletion and on several animal studies which are discussed. Providing that our hypothesis will be validated by an analogous tyrosine depletion study and additional preclinical studies, the next logical step would be to directly test our hypothesis in patients. Possible criteria for patient selection, ethical issues and locus of DBS are carefully discussed.