The current treatment of depression, based on conventional antidepressant drugs that influence monoaminergic systems, is not satisfactory, and innovative antidepressant drugs are still needed. The next generation of treatments needs to be more effective, faster-acting and better tolerated than currently used antidepressants. A growing body of evidence indicates that compounds that modulate the glutamatergic system may be a group of novel and mechanistically distinct agents for the treatment of depression. Both preclinical and clinical data show strong, rapid and sustained effects of the NMDA receptor antagonist ketamine in treatment-resistant depression. However, ketamine cannot be considered as a novel antidepressant drug because of its side-effects and abuse potential. Because glutamatergic transmission is controlled not only by ionotropic but also by metabotropic glutamate receptors, their involvement in the etiology and the therapy of depression has also been postulated. Here, we review data supporting the potential antidepressant activity of mGlu5 receptor antagonists as well as the involvement of mGlu5 receptors in the pathophysiology of depression.