Ziprasidone is a newer "atypical" or "second-generation" antipsychotic. Oral ziprasidone (ziprasidone hydrochloride) has been approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia, and acute manic or mixed episodes associated with bipolar disorder (with or without psychotic features). Comparisons with other second-generation antipsychotics in meta-analyses reveal similar efficacy to that observed for quetiapine or aripiprazole, but inferior efficacy to that of olanzapine or risperidone in the treatment of schizophrenia. However, the rate of dose titration and the dose achieved may have an important bearing on ziprasidone's efficacy profile, with a target dose range of 120-160 mg/day being associated with optimal symptom control and greater persistence with treatment. In addition, enhancing ziprasidone's effectiveness requires ensuring that ziprasidone is administered with a 500 kcal meal; otherwise, absorption of oral ziprasidone is substantially reduced and cannot be compensated for by increasing the prescribed dose. Regarding tolerability, ziprasidone has important advantages in that it is not associated with clinically significant weight gain or adverse changes in cholesterol, triglycerides, or glycemic control, and patients may experience moderate improvement in these measures when switching to ziprasidone from a different antipsychotic. Ziprasidone also lacks significant persistent effects on prolactin levels, is not anticholinergic, and only infrequently causes extrapyramidal side effects or postural hypotension; however, it can be associated with somnolence. Ziprasidone may prolong the electrocardiogram (ECG) QT interval but this does not appear to pose a substantial clinical problem. Provided that an adequate dose of ziprasidone is prescribed, and administered with a 500 kcal meal, ziprasidone can be effectively used to control symptoms without the long-term liabilities of metabolic side effects.