Depression is the most common mental illness characterized by anhedonia, avolition and loss of appetite and motivation. The majority of conventional antidepressants are monoaminergic system selective inhibitors, yet the efficacies are not sufficient. Up to 30% of depressed patients are resistant to treatment with available antidepressants, underscoring the urgent need for development of novel therapeutics to meet clinical needs. Recent years, compounds acting on the glutamate system have attracted wide attention because of their strong, rapid and sustained antidepressant effects. Among them, selective inhibitors of metabotropic glutamate receptors 2 and 3 (mGluR2/3) have shown robust antidepressant benefits with fewer side-effects in both preclinical and clinical studies. Thus, we here attempt to summarize the antidepressant effects and underlying mechanisms of these inhibitors revealed in recent years as well as analyze the potential value of mGluR2/3 selective inhibitors in the treatment of depression.