To provide a narrative review based on clinically relevant evidence specific to the issues surrounding the use of the second generation antipsychotics in schizophrenia.MEDLINE and Cochrane Library searches were performed to identify literature pertinent to the available and anticipated novel antipsychotics in North America. Articles that were selected included clinical trials, clinical practice guidelines, reviews and pharmacoeconomic analyses researching the efficacy and safety of the second generation antipsychotics including comparative studies among these agents. Related editorials, letters and newsletter commentaries were reviewed from a variety of sources to provide enhanced depth.Following the advent of clozapine in the 1980s, three other second generation antipsychotics (risperidone, olanzapine and quetiapine) have become available, with others (eg, ziprasidone) expected in the near future. The single major advance with these agents is their reduced propensity for extrapyramidal side effects and tardive dyskinesia. However, clinicians should be aware of the differential risk for these side effects. The purported advantage for negative symptoms compared with conventional agents has been inconsistent and may not be clinically important.The availability of a wide selection of antipsychotics has heralded the possibility of more effective management of the complex symptoms of schizophrenia. However, this has also made the choice of optimal treatment difficult. It is essential that practitioners understand how these agents compare with each other and with conventional antipsychotics.