Major depressive disorder affects nearly 20% of people during their lifetime. A growing body of evidence supports the theory that neuroinflammation plays a prominent role in the neurobiology of depression, which implicates glutamate and gamma aminobutyric acid as key factors in the pathophysiology of the disease process. This article reviews the pathologic pathways of glutamate excess in the central nervous system and how they may be implicated in the underlying disorder of treatment-resistant depression and targeted for treatment.