Abstract In a substantial proportion of people with schizophrenia the illness shows a poor response to antipsychotic medication. Failure to achieve remission even after the first episode is limited to relatively few cases, and more commonly patients become progressively unresponsive to medication. There are no reliable predictors of treatment-resistant schizophrenia (TRS), and the condition defies delineation in terms of symptom profile or neurobiological features. Indeed, it remains to be determined whether TRS should be considered as a distinct subtype of schizophrenia or viewed simply as the more severe end of the illness spectrum, characterized by refractory symptoms and poor integration into the community. Despite recent advances in pharmacotherapy, and new data on the clinical effectiveness of clozapine, the clinical care and management of people with TRS continue to present a major clinical challenge. In this article, we present a concise clinical review of TRS, with discussion of the different and evolving definitions, the clinical assessment, and the evidence for pharmacological and non-pharmacological strategies.