Clozapine represented the first significant advance in the pharmacotherapy of schizophrenia since the introduction of conventional antipsychotic drugs in the 1950's. Despite its superior efficacy and potential to reduce substantially the morbidity of schizophrenia and improve the outcomes, of patients, clozapine has not been used on a widespread basis or as a first-line treatment due to its potential for agranulocytosis. With the introduction of risperidone and the imminent prospect of other atypical antipsychotic drugs (olanzapine, sertindole, quetiapine, ziprasidone), clinicians may be able to improve dramatically the methods and manner in which they treat schizophrenia and related psychotic disorders. If we accept the premise that atypical antipsychotic drug provide superior efficacy, reduced side effects, and the prospect of better compliance, their greatest impact may be when used in patients at the beginning of their illness. The following article provides a rationale and hypothesis for the use of atypical antipsychotic drugs as a first-line treatment of schizophrenia.