There has been a veritable explosion of research conducted for interventions that may be advantageous for the management of treatment-refractory schizophrenia. After a discussion of how to define treatment resistance or treatment refractoriness, obstacles to its accurate identification are presented. Randomized clinical trials that have tested antipsychotic monotherapies, antipsychotic combination therapies, nonantipsychotic augmentation strategies and nonpharmacological interventions are catalogued. Although clozapine has been a landmark medication, attempts to augment it have not resulted in any further breakthroughs of the same magnitude. Some logical candidates for augmentation have not been successful, including anticholinesterase inhibitors and other agents used to treat cognitive decline in Alzheimer’s disease. Antipsychotic combinations have resulted in incremental improvements at best. Research being done with antidepressant medications and with agents that impact on the glutamate receptor holds the greatest promise at this time.