OBJECTIVE To clarify the role of 'melancholia' in psychiatric nomenclature. Most clinicians and researchers are convinced that the syndrome currently termed major depressive disorder encompasses multiple subgroups that differ meaningfully in phenomenology, natural history, treatment response, and pathophysiology. Delusional depression and melancholia have attracted the most empirical work, but efforts to define the latter condition have declined in recent years following a number of failures to show the validity of the melancholic/nonmelancholic distinction. METHODS Review of experience. RESULTS Beyond the DSM-IV symptom profile, melancholia has been associated with greater overall severity, a low likelihood of placebo response, an episodic course, a family history of depression without alcoholism, a relatively healthy personality, and hypothalamic-pituitary-adrenal axis hyperactivity. Evidence for the validity of the melancholia concept lies in the fact that the presence of each of these characteristics has been shown to increase the likelihood of one or more of the others. CONCLUSIONS A diagnosis of melancholia may eventually prove valuable in treatment selection, but the necessary evidence will not be forthcoming until a widely accepted definition exists that is both inherently valid and that can be applied consistently across research sites.