The treatment of patients with drug-resistant schizophrenia is a major challenge for both the clinician and the patient, and requires systematic and comprehensive management.Patients should initially be assessed to clarify that they are resistant to therapy, as opposed to noncompliant or undertreated. The dosage of existing antipsychotic should be increased. If no response is observed or intolerable adverse effects occur, an alternative typical antipsychotic should be tried. In the event of nonresponse to this alternative agent, a trial with clozapine (an atypical antipsychotic) can be initiated. In patients failing to respond to any single antipsychotic, there are some alternative somatic treatments often used in combination with antipsychotics. These include lithium, carbamazepine, benzodiazepines, &bgr;-adrenergic receptor antagonists, levodopa, reserpine and some antidepressant medications.The reasons for nonresponsiveness are not solely drug related, with psychological and social factors also contributing. Therefore, non-drug strategies, i.e. psychological and social methods, should be used in combination with pharmacological treatments to offer the patient the most consistent benefit.The results of all types of treatment should be evaluated regularly and carefully to allow clear conclusions concerning potential benefits to be made.