Depression represents one of the most profound human problems currently facing the global health care system. It is a prevalent clinical condition and is estimated to rival virtually every other known medical illness in burden of disease morbidity early in this millennium. Understanding the chronic nature of this illness is key to the development of a more informed, longitudinal perspective on the diagnosis and treatment of depression. In this report, the morbid impact of depression is reviewed, from the perspectives of illness symptoms, societal impact, and emerging evidence of critical neurobiological consequences of the untreated condition. Reconceptualizing major depression from this longitudinal and multidimensional perspective is crucial to providing an effective response to this critical public health challenge.