Clozapine is a second generation antipsychotic indicated for patients with treatment-resistant schizophrenia (TRS). TRS is schizophrenia that does not respond fully to conventional schizophrenia treatments, including first-line antipsychotics. According to the Canadian Schizophrenia Guidelines (CSG), treatment-resistance is indicated after failure of two antipsychotics, although definitions of TRS vary among clinical trials. It has been estimated that in patients receiving conventional pharmacotherapy for schizophrenia, 50% of these patients do not respond adequately to prescribed pharmacotherapy (30% may exhibit a partial response, and 20% may exhibit no response). Clozapine is associated with a variety of side-effects, including drowsiness, dizziness, tachycardia (high resting heart rate), constipation, weight gain, lowered white blood cell count, and excess saliva production. Serious side effects include myocarditis, pericarditis, neutropenia, cardiomyopathy, and death. Some side effects, such as myocarditis, can occur relatively quickly (within two weeks) after initiation of the medication. Clozapine must be initiated at a low dose and titrated up to the therapeutic dose over time to avoid side effects. Therapeutic doses can range from 200 mg to 450 mg per day and are generally not exceeding 900 mg per day (although doses of more than 900 mg per day are possible). Initiation of clozapine may start as low as 12.5 mg per day, titrating upwards until individual effectiveness is seen (for example, resolution of psychosis symptoms). Initiation on clozapine requires strict monitoring protocols to ensure compliance and to address the side effects associated with the medication. For example, in the United States, the Clozapine Risk Evaluation and Mitigation Strategy requires all prescribers and pharmacies to be certified in order to prescribe or dispense clozapine. Part of the Clozapine Risk Evaluation and Mitigation Strategy program includes regular absolute neutrophil counts for patients on clozapine to monitor for neutropenia. In Canada, after reintroduction of clozapine in 1991 (after removal from the market in 1975 because of reported infections due to low white blood cell counts), patients were required to join a patient registry program (e.g., Sandoz Clozapine Risk Management Program) to monitor white blood cell counts. When switching to a new brand of clozapine, patients must join the manufacturer-specific registry upon changing medications. Guidelines outlining appropriate use of clozapine are important to ensure timely, safe, and suitable prescribing of clozapine in a variety of settings. The objective of the current review is to summarize clinical effectiveness of clozapine during the initiation phase of treatment in adult patients with schizophrenia and summarize recommendations regarding monitoring of adult patients during this initiation phase.