Major depressive disorder (MDD) is a common, chronic, recurrent mental illness that affects millions of individuals worldwide. To date, the monoaminergic systems (serotonin, norepinephrine, and dopamine) have received the most attention in the neurobiology of MDD, and all classes of antidepressants target these monoaminergic systems. Accumulating evidence suggests that the glutamatergic system plays an important role in the neurobiology and treatment of this disease. Some clinical studies have demonstrated that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant patients with MDD. Here, the author reviews the recent findings on the role of the glutamatergic system in the neurobiology of MDD and in new potential therapeutic targets (NMDA receptors, AMPA receptors, metabotropic glutamate receptors, ceftriaxone, minocycline, N-acetyl-L-cysteine) for MDD.