Treatment-resistant schizophrenia (TRS) occurs in up to 30% of patients with schizophrenia and is defined as the persistence of positive symptoms despite ≥2 trials of antipsychotic (AP) medications at adequate doses and duration with documented adherence. Patients may be treatment resistant at the first-episode of psychoses or develop resistance over time via ≥1 neurobiological pathways, potentially due to relapse. The dopamine supersensitivity hypothesis of TRS posits that dopamine D2 receptor upregulation due to long-term blockade with AP medications may negatively affect treatment response. However, not all individuals with schizophrenia have dopamine supersensitivity after long-term AP exposure, and other abnormalities such as those occurring in glutamatergic or other neurochemical pathways may underlie treatment resistance in these patients. The neurobiological etiopathogenetic diversity of TRS suggests that a flexible, biologically based approach is needed to treat the condition. Early recognition and effective treatment are important, as is a better pathophysiologic understanding of TRS with the following clinical and research implications: 1) Prospective, empirical trials with different drug classes (including early use of clozapine) may be needed to achieve symptom relief in patients with persistent symptoms despite proven AP medication adherence. 2) Biomarkers for TRS subtypes should be identified/evaluated. 3) New drugs should be developed to treat TRS based on specific treatment-resistant psychopathological domain vs the current “one-size-fits-all” approach. Further research characterizing the pathophysiology of TRS will inform improved treatment strategies and facilitate the development of new medications and/or treatment algorithms to more effectively treat patients with TRS based on underlying neurobiological profile.