Atypical antipsychotics are a major advance in the management of schizophrenia. The reevaluation of widely held risk/benefit assessments of the various atypical antipsychotics provides an opportunity to improve treatment patterns. The best available clinical trial evidence indicates that efficacy among the atypical antipsychotics (at equivalent doses) is very similar, but safety and tolerability profiles differ significantly. Atypical antipsychotics differ markedly in their potential to cause metabolic disturbances, including obesity, diabetes, dyslipidemia, and the metabolic syndrome; clozapine and olanzapine carry the greatest risks, atypical antipsychotics like risperidone and quetiapine have lower risks, and newer agents like ziprasidone and aripiprazole are associated with minimal metabolic risks. Results from the Atypical Antipsychotic Therapy and Metabolic Issues (AtAMI) survey define important opportunities for improving medical and psychiatric outcomes during atypical antipsychotic therapy. (See accompanying article by Newcomer et al) Additional educational and research efforts are required to increase understanding of common conditions such as the metabolic syndrome, increase awareness of uncommon but serious events like diabetic ketoacidosis, and pancreatitis, and identify appropriate strategies for monitoring the risks/benefits of atypical antipsychotic therapy. As clinicians refine practice patterns regarding the atypical antipsychotics, they may require additional knowledge and resources to fully incorporate risk/benefit considerations and optimize long-term psychiatric and medical outcomes.