A large proportion of patients with schizophrenia show a poor response to first-line antipsychotic drugs, which is termed treatment-resistant schizophrenia. Previous studies found that a different neurobiology might underlie treatment-resistant schizophrenia, which necessitates the development of different therapeutic approaches for treating treatment-resistant schizophrenia. This study reviewed previous studies on the pathophysiology of treatment-resistant schizophrenia and the pharmacological intervention, and forthcoming investigations of treatment-resistant schizophrenia are suggested.