Through the use of polysomnographic, epidemiologic, and prospective clinical follow-up studies, the authors document that the course of major depressive disorder (MDD) is expressed by fluctuating symptoms in which depressive subtypes included in official diagnostic systems do not represent discrete disorders, but are stages along a dimensional continuum of symptomatic severity. Depressive symptoms at the major, minor, dysthymic or otherwise sub-threshold levels are all integral components of the longitudinal clinical structure of MDD with each symptom level representing a different phase of illness intensity, activity and severity. Detailed analyses indicate that patients are symptomatic 60 % of the time, much of it at the minor, dysthymic or subthreshold level. The symptomatic phases of illness activity are interspersed sporadically with inactive phases, when patients are asymptomatic. These findings are pertinent to both clinical cohorts and community-based epidemiologic samples. Each level of depressive symptom severity is associated with significant psychosocial impairment; such impairment increases progressively with each stepwise increment in symptom severity. When patients are asymptomatic their psychosocial functioning returns to good or very good levels. Residual subthreshold symptoms in the course of MDD are associated with high risk for early episode relapse and a significantly more chronic course of illness. Asymptomatic recovery from MDD is associated with significant delays in episode relapse and recurrence and a more benign course of illness. We submit that, as in the case of chronic medical conditions, the goal of treating unipolar depressive illness should optimally be to return the patient to as asymptomatic a level as is feasible by all available therapeutic means.