Major depressive disorder or “unipolar depression” is a common condition likely related to several etiologies. Recent research has focused on the biological underpinnings of major depressive disorder as well as treatment advances, involving both pharmacotherapy and psychotherapy. In this chapter, the epidemiology, clinical picture, biological theories regarding etiology, clinical presentation in primary care and mental health jhysettings, and treatment of major depressive disorder are reviewed. Advances in genetic approaches to understanding the pathogenesis of major depressive disorder will likely result in better and more precise treatments in the future. The chapter on this topic in the previous iteration of this book was titled “Unipolar Depression” and was written by one of my mentors, George Winokur. Much of our current understanding of mood disorders emanates from the research of Winokur and his colleagues. I am delighted to have the opportunity to write this chapter. The term “unipolar depression” evolved from the concept of a primary affective disorder. Primary affective disorder referred to patients whose first psychiatric disorder was depression and who did not evidence manic or bipolar symptoms. Support for the classification of primary affective disorder derived from the classic study of Cassidy et al. citech05:bib01, and symptoms differentiating depressed patients from control subjects formed the basis of the disorder. Symptoms that occurred in more than 50 of depressed patients included reduced energy, impaired concentration, anorexia, initial insomnia, loss of interest, difficulty starting activities, worrying, subjective agitation, slowed thinking, difficulty making decisions, terminal insomnia, suicidal ideation or plans, weight loss, tearfulness, slowed movements, irritability, and feeling one will never get well cite ch05:bib02 . These symptoms continue to form the basis for the diagnosis of depressive states, and the clinical classifications used by the Washington University group were summarized by Feighner et al. cite ch05:bib03 . Winokur cite ch05:bib04 further proposed that unipolar depression might be divided into three groups: “ depression spectrum disease”—individuals who were depressed and had a first-degree relative who had alcoholism or antisocial personality disorder; “familial pure depressive disease”—depressed individuals who had a family history of depression but not of alcoholism or antisocial personality disorder; and “sporadic depressive disease”—depressed individuals who had no family history of depression, alcoholism, or antisocial personality disorder. This classification system is no longer in clinical use but is of interest in that it was one of the first clinical classifications in psychiatry to use both clinical symptoms and family history.