Pharmacotherapy of schizophrenia presents a set of challenges. Ideally, antipsychotic therapy should have a rapid effect on clinical improvement, show effectiveness against symptoms in multiple domains, and possess a tolerability profile that optimizes patient adherence and overall health outcomes. The atypical antipsychotic ziprasidone has been shown in placebo- and active-comparator-controlled clinical studies to be effective in treating the positive, negative, and affective symptoms of schizophrenia. In placebo-controlled trials of 4 to 6 weeks, significant improvements in overall psychopathology and negative symptoms as early as 1 week after treatment initiation were demonstrated. In trials of 4 to 8 weeks' duration in patients with acute exacerbation of schizophrenia, ziprasidone demonstrated efficacy comparable to that of haloperidol, olanzapine, and risperidone. In a 12-week study of patients with treatment-resistant schizophrenia, ziprasidone demonstrated overall efficacy comparable to that of chlorpromazine, with superior improvement in negative symptoms. In 6-week, open-label switching studies, patients switched to ziprasidone from conventional antipsychotics, olanzapine, or risperidone because of suboptimal efficacy or tolerability experienced improvement in symptoms. Oral ziprasidone's tolerability profile includes a lower movement disorder burden than that of risperidone, a lower liability for weight gain than that of risperidone or olanzapine, and an absence of significant deleterious effects on serum lipid levels or glucose metabolism. Available clinical data support rapid titration to > or = 120 mg/day for optimal efficacy in patients with acute exacerbation of schizophrenia.