Objective: To review clozapine's position in treatment algorithms for schizophrenia.Method: Clozapine's status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects. Results:The hematologic monitoring implemented with clozapine's reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials.Conclusions: Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination.Can J Psychiatry. 2010;55(10):677-684. Clinical Implications· Although clozapine has demonstrated superiority to other antipsychotics in refractory schizophrenia, it remains underprescribed and delayed in its use.· A large body of recent data, in combination with current safety measures, confirms that clozapine-induced agranulocytosis and related deaths are very rare.· Clozapine's unique clinical profile in refractory schizophrenia challenges delayed access to its use. Limitations· The data in this review are relevant and applicable only in the countries where clozapine safety measures are in place. · Clozapine's clinical superiority appears specific to refractory schizophrenia. · Use of clozapine earlier than third-line treatment requires a re-evaluation of how refractory schizophrenia is currently defined.

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