The introduction of clozapine to the pharmacological armamentarium has led to a redefinition of antipsychotic drugs as a class. Clozapine represents the first genuinely atypical antipsychotic drug from both a clinical and a pharmacological perspective. Despite its clinical advantages, the use of clozapine has been limited by a propensity to induce agranulocytosis in 1% of the patients who are treated with this compound. This article reviews the indications for clozapine treatment and the present knowledge base regarding the incidence, monitoring and management of agranulocytosis.As agranulocytosis cannot be prevented, knowledge of risk factors is important. The risk factors that have been delineated include: increasing age, female gender, specific human leucocyte antigen (HLA) halotypes and the duration of exposure to clozapine (with 76% of cases occurring between week 4 and week 18). Among the patients who develop agranulocytosis, the risk of death is approximately 2%. In addition to agranulocytosis, patients receiving clozapine may manifest several benign and asymptomatic blood dyscrasias including leucocytosis, lymphopenia, eosinophilia and thrombocytosis.White blood cell counts must be followed weekly for the first 18 weeks of treatment and less frequently (every 2 or 4 weeks) thereafter in all patients receiving clozapine (in the US, white blood cell counts must be followed weekly for the duration of clozapine treatment). Assessment should be more frequent when there is a downward trend in the absolute neutrophil count. There is also evidence for the occurrence of a white blood cell upward spike prior to a decline in this parameter. This latter finding has been shown to be highly sensitive, but only moderately specific.If agranulocytosis does occur, a bone marrow aspiration and the addition of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor may be indicated.The psychiatric management of patients receiving clozapine who develop agranulocytosis often entails psychiatric hospitalisation. Rechallenge of these patients with clozapine is contraindicated. Risperidone may offer a clinical alternative after the patients have recovered haematologically.The mechanisms of clozapine-induced agranulocytosis remain unknown, however there are several postulated mechanisms. These include a direct toxic effect on the bone marrow, the formation of toxic free radicals, or an immunemediated mechanism involving the formation of antigranulocyte or antimyeloid antibodies.