Major depressive disorder (MDD) is a common neuropsychiatric disorder affecting the mood and mental well-being. Its pathophysiology remains elusive due to the complexity and heterogeneity of this disorder that affects millions of individuals worldwide. Chronic stress is frequently cited as the one of the risk factors for MDD. To date, the conventional monoaminergic theory (serotonin, norepinephrine, and/or dopamine dysregulation) has received the most attention in the treatment of MDD, and all available classes of antidepressants target these monoaminergic systems. However, the contributions of other neurotransmitter systems in MDD have been widely reported. Emerging preclinical and clinical findings reveal that maladaptive glutamatergic neurotransmission might underlie the pathophysiology of MDD, thus revealing its critical role in the neurobiology of MDD and as the therapeutic target. Aiming beyond the monoaminergic hypothesis, studies of the neurobiological mechanisms underlying the stress-induced impairment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-glutamatergic neurotransmission in the brain could provide novel insights for the development of a new generation of antidepressants without the detrimental side effects. Here, the authors reviewed the recent literature focusing on the role of AMPA-glutamatergic neurotransmission in stress-induced maladaptive responses in emotional and mood-associated brain regions, including the hippocampus, amygdala, prefrontal cortex, nucleus accumbens and periaqueductal gray.