Magnesium and copper are important modulators of NMDA-receptor activity. Recent data indicate that disturbances of glutamatergic transmission (especially via NMDA-receptor) are involved in pathogenesis of mood disorders. Magnesium deficiency, the same as disturbances in turn over of copper, are related to a variety of psychological symptoms especially depression. There are many reports indicating significant changes in blood levels of magnesium or copper during a depressive episode. Moreover magnesium exhibits antidepressant-like and anxiolytic-like effects in animal models of depression, in rodents. This article reviews the alterations in central and peripheral magnesium and copper homeostasis in relation to pathophysiology and treatment of depression.