Abstract : Despite the availability of several antidepressants, the treatment of major depression is far from being satisfactory. With conventional antidepressants, more than 30 to 45 % of the patient will not respond or present only partial remission. In the prospect of a better treatment of depression, research tends to develop original molecules, more effective, with a faster onset of action and a better tolerability. The new targets of antidepressive pharmacotherapy are beyond the membrane receptor. The future in the treatment of depression requires a better understanding of cellular and molecular mechanisms involved in the pathophysiology of depression and biochemical mechanisms explaining the antidepressive effect. In this context, the glutamatergic system plays a role in the pathophysiology of depression. Agents modulating glutamatergic activity could act as antidepressants.