Ziprasidone was the fifth atypical antipsychotic approved by Food and Drug Administration (FDA) for use in bipolar mania and mixed episodes. This atypical antipsychotic has a unique profile, as it acts primarily through serotonergic and dopaminergic receptor antagonism, but also exerts effects as an inhibitor of norepinephrine reuptake. Moreover, one of the advantages of ziprasidone is its safety profile as it is not associated with clinically significant metabolic side effects and little or no effect on prolactin level or anticholinergic side effects. Most of the studies evaluating ziprasidone's efficacy and safety are short-term double-blind, placebo-controlled studies in acute mania and mixed episodes. In two of them, ziprasidone was associated to significant improvement in the primary measures assessed. However, an add-on study, lithium plus ziprasidone showed similar results than lithium monotherapy, although there was a significant advantage for the combination within the first week. In a more recent trial, ziprasidone was compared with placebo and haloperidol as monotherapies, again beating placebo. In that trial, ziprasidone appeared to be safer and better tolerated, although less likely efficacious than haloperidol. Particularly, subjects treated with ziprasidone were less likely to switch to depression. Despite the well-studied efficacy of ziprasidone in the first weeks of treatment, there are no controlled trials that evaluate the role and efficacy of ziprasidone in long-term treatment of bipolar disorder (BD). Overall, in the open-label extension studies, there was a global improvement at all visits compared with baseline scores. Furthermore, ziprasidone appears to offer some antidepressant effect in patients with major depressive episode and resistant to treatment, as demonstrated in add-on open-label studies with ziprasidone plus selective serotonin reuptake inhibitor (SSRI).