Antidepressant therapy exhibits low clinical efficacy and produces a variety of unwanted side effects. Therefore, the search for more effective antidepressants is still in progress. Antidepressant properties of magnesium and zinc have been demonstrated in animal screen tests/models and clinical studies. Moreover, these bio-elements enhance antidepressant activity of conventional antidepressants in these behavioral paradigms. As for magnesium, clinical studies demonstrated equivocal results concerning its supplementary effectiveness in the treatment of depression. Generally, some depressed patients with hypomagnesemia responded very well to such supplementation, whereas response of other patients was weaker. Clinical data on the effectiveness of zinc supplementation in the therapy of depression are much more robust. A number of studies demonstrated enhancement of the efficacy of pharmacotherapy by zinc supplementation in major depression. What is important, recent studies demonstrate that zinc supplementation augments efficacy of antidepressants also in treatment-resistant patients. All the available data indicate the importance of magnesium and zinc in the therapy of depression.