Early and effective treatment in first-episode schizophrenia is associated with better outcomes. Evidence suggests that response is generally robust in a first antipsychotic trial, but a marked reduction in response rate is observed among patients for whom a second trial is warranted, and even further reductions are seen in subsequent trials. Clozapine, the treatment of choice in refractory schizophrenia, is routinely employed only as a third-line treatment, and it has been shown to markedly enhance the rate of response, even when compared with other atypical antipsychotics. This raises the question of whether clozapine would be more effectively positioned as a first-line treatment. Current evidence addressing this question does not support this position, although the limited data available and methodological issues preclude a firm conclusion. Practical issues related to clozapine use, in combination with the robust response reported for other agents when used as first-line treatment, certainly call into question the likelihood that clozapine would be chosen if it were an option at this stage. In contrast, the notable reduction in response rate to second-line treatments, coupled with clozapine’s substantial response rate in refractory schizophrenia and evidence indicating better outcomes with early, effective treatment, makes a compelling argument for research examining clinical and functional outcomes with clozapine positioned as a second-line treatment.