Depression is one of the most prevalent diseases in the world today. Ten percent of the U.S. adult population suffers with the illness every year, with many persons receiving either no or inadequate treatment. Psychiatrists know depression as an illness that affects the mind and mood of a sufferer, altering that person’s core experience of others and the world around them. But now, research convincingly shows that significant morbidity and mortality are associated with the primary manifestations of depression beyond that occasioned by the disturbed affect. Patients with major depression have a doubling of mortality at any age, independent of suicide, smoking, or other risk factors for poor health. There is emerging evidence that depressed patients have a significant loss of cells in the prefrontal cortex, a brain area important in discerning reward versus punishment, in shifting mood from one state to the other, and in exerting cortical restraint on the amygdala fear system through the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. An increase in cortisol and norepinephrine secretion represents a highly adverse biochemical environment, a condition that is likely to contribute to many different adverse outcomes, including increased visceral fat, insulin resistance, increased inflammation, enhanced blood coagulation, deficient fibrinolysis, decreased bone formation, and increased bone resorption. These changes support the concept of depression as a systemic disease that may have primary medical manifestations. Moreover, depression has adverse effects on comorbid medical diagnoses as well, such as coronary artery disease, diabetes, and osteoporosis. Indeed, emerging data have shown that prospective treatment of depression in patients who have experienced myocardial infarction increases chances of a good medical outcome and survival. Thus, detection of depression in all ill persons is critical, and the pursuit of new and more effective treatments for depression will increase psychological, psychiatric, and medical health worldwide.