Previously, clinicians could only utilize antipsychotic drugs that almost invariably caused extrapyramidal side effects (EPS) at the dose at which they were clinically effective. By definition, second-generation atypical antipsychotic agents are significantly better than conventional agents with regard to EPS; that is, they are clinically effective at doses at which they are less likely to cause EPS. This advantage 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 clinical advantages provided by this class of atypical antipsychotics. Pharmacologically, “atypical” antipsychotics differ in their side-effect profiles. Six second-generation antipsychotics are currently available in the United States: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. There are meaningful differences between these agents with regard to weight gain, sedation, anticholinergic side effects, cardiovascular issues, endocrine side effects, and hepatic and sexual issues; these are considered and their clinical implications discussed.