Inadequate treatment contributes not only to poor quality of life but also to an increase in disease-related societal burdens. A small subset (20–30%) of the schizophrenia patient population are treatment-resistant and financially cost approximately ten-fold more than non-treatment-resistant schizophrenia patients . Numerous ineffective antipsychotic trials continue to be prescribed while clozapine, which has widespread compelling efficacy data, continues to be underutilized in treatment-resistant schizophrenia. This chapter addresses clozapine efficacy in not only treatment-resistant psychosis but also comorbid suicidality and aggression, as well as treatment-resistant mania. Further, initiation and maintenance of clozapine treatment is summarized.