The glutamate hypothesis, a theory that emerged in 1980, suggests that its receptors are promising drug targets for treating treatment-resistant schizophrenia. Research in this field has been conducted through various methods, including genetics, postmortem brain studies, animal models, and neuroimaging. Notably, proton magnetic resonance spectroscopy (1H-MRS) has become one of the most reliable techniques not only for identifying future drug targets but also for elucidating the pathophysiology of this disease. To date, several meta-analyses on 1H-MRS studies in schizophrenia have reported lower glutamate levels in the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) in the patient group compared to healthy controls. These findings may explain potential neurocircuits observed in animal models of schizophrenia, yet more data are needed for a comprehensive understanding. The development of drugs targeting mGluR2/3, a metabotropic glutamate receptor, showed promise by passing phase 2 clinical trials but ultimately failed in phase 3. Despite these setbacks, the exploration of the glutamatergic system remains a central focus for the future of schizophrenia research, underscoring the continued need for data accumulation.