Despite the advances achieved since the introduction of chlorpromazine, schizophrenia may respond inadequately to standard drug treatments. The reasons for this include noncompliance, poor tolerance and the development of distressing side effects or the resistance of the illness itself. Treatment-resistant schizophrenia is increasingly the focus of new research developments. The older or classic antipsychotic drugs have a broad spectrum of action on central and peripheral nervous system receptors. Their action on dopamine receptors was an early clue to the pathogenesis of schizophrenia. More recently, multiple subtypes of dopamine receptors have been identified. These, plus serotonin receptors, have been identified in brain structures thought to be implicated in schizophrenic illnesses. Atypical antipsychotic agents whose pharmacological action is either more specific, or which have novel receptor binding profiles show characteristic effects in both animal models and clinically. These drugs may improve symptoms in otherwise resistant illness or where intolerance prevents the use of standard treatments. There are a number of adjunctive somatic treatment strategies using established agents such as lithium and electroconvulsive therapy the use of which is now being explored systematically. The most exciting current development is the re-emergence of clozapine as a highly effective atypical antipsychotic drug which can be used safely if special surveillance is undertaken to monitor for its potentially severe toxic effects. These recent advances offer hope of improvement in the prognosis of people suffering from severe and intractable forms of schizophrenia.