Between 20% and 40% of schizophrenic patients are thought to be resistant to conventional antipsychotic therapy, although this may be an underestimate of the scale of the problem. The causes of nonresponsiveness are likely to be multifactorial, and there have been reported associations between refractoriness and neuropsychological impairment, negative symptoms, and abnormal brain morphology. For some patients, treatment resistance may in fact represent an intrinsic part of the schizophrenic illness. Treating the refractory patient should begin with a full, preferably multidisciplinary, review of diagnosis, symptoms, and side effects. Although an increased dose of a conventional antipsychotic agent can be effective for some patients, consideration should be given to reducing the dose and combining treatment with psychosocial management, or switching to one of the newer atypical antipsychotics.