This chapter discusses DSM and non-DSM definitions and approaches to mood illness. Before 1980, the concept of manic–depressive illness (MDI) meant both bipolar illness and recurrent unipolar depression. Evidence on diagnostic validators since 1980 has not strengthened that claim and may be interpreted to support the original MDI concept, that is, that bipolar illness and unipolar depression are part of the same overall disease (MDI). As a corollary, the concept of major depressive disorder (MDD) may represent a spectrum of different depressive subtypes: mixed (depression with manic symptoms), melancholic, pure, vascular, and neurotic depression. Each subtype differs from the other, based on diagnostic validators of course, genetics, and biological aspects and/or treatment effects. The scientific evidence for this heterogeneity of MDD appears to weaken the claim dating to DSM-III in 1980 that this condition is a different diagnosis/illness from bipolar disorder. The differential diagnosis of mood conditions is described.