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Previously, clinicians worked with antipsychotic drugs that almost invariably caused extrapyramidal side effects (EPS) at the dose at which they were clinically effective. By definition, all newer generation atypical antipsychotic agents are significantly better than conventional agents with regard to EPS; i.e., they are clinically effective at doses at which they do not cause EPS. This EPS advantage of atypical antipsychotics translates into several important clinical benefits, including better negative symptom efficacy, lesser dysphoria, less impaired cognition, and a lower risk of tardive dyskinesia; in fact, this “EPS advantage” is the principal basis of the many clinical advantages provided by the class of atypical antipsychotics. While all atypical agents share this “EPS advantage,” there are important differences between these agents with regard to the ease and consistency with which this EPS advantage can be realized. Pharmacologically, different atypical antipsychotics differ; these differences translate into differences in their side effect profiles. Five atypical antipsychotics are currently available: clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. Meaningful differences between these agents with regard to weight gain, sedation, anticholinergic side effects, cardiovascular issues, endocrine side effects, hepatic and sexual issues, will be considered and their clinical implications discussed.