The treatment and management of neuroleptic-resistant schizophrenic patients, who comprise 5 to 25 percent of all patients with that diagnosis, are major problems for psychiatry. In addition, another large group of schizophrenic patients, perhaps 5 to 20 percent, are intolerant of therapeutic dosages of neuroleptic drugs because of extrapyramidal symptoms, including akathisia, parkinsonism, and tardive dyskinesia. Because about 60 percent of neuroleptic-resistant schizophrenic patients respond to clozapine and a large percentage of neuroleptic-intolerant patients are able to tolerate clozapine, it should be considered the treatment of choice for such patients until other therapies are proven to be superior. A trial of clozapine alone should usually be continued for up to 6 months before it is terminated or supplemental agents are tried. Plasma levels of clozapine may be useful to guide dosage. The major side effects of clozapine are granulocytopenia or agranulocytosis (1%-2%) and a dose-related increase in the incidence of generalized seizures. Psychosocial treatments such as education of the patient and the family about the nature of the illness, rehabilitation programs, social skills training, and assistance in housing are generally needed to obtain optimal benefit from clozapine, as with other somatic therapies. If clozapine is unavailable, unacceptable, or not tolerated, a variety of approaches may be employed to supplement typical antipsychotic drugs for patients who do not respond adequately to these agents alone. These include lithium; electroconvulsive therapy; carbamazepine or valproic acid; benzodiazepines; antidepressant drugs; reserpine; L-dopa and amphetamine; opioid drugs; calcium channel blockers; and miscellaneous other pharmacologic approaches. The evidence for the efficacy of these ancillary somatic therapies in treatment-resistant patients is relatively weak. Polypharmacy should be tried only for discrete periods and with clear goals. If these are not achieved, supplemental medications should be discontinued. Psychosurgery is not a recommended alternative at this time.