Ziprasidone, a benzisothiazolyl piperazine derivative of tiospirone, is a second-generation antipsychotic with high-affinity antagonism for 5-hydroxytryptophan (5HT)(2A), 5HT(2C), 5HT(1D) and D(2) receptors, pre- and post-synaptic agonism for 5HT(1A) receptors, and inhibition of reuptake for serotonin and norepinephrine. Initially approved for the treatment of adults with schizophrenia, ziprasidone has more recently received supplementary indications for acute manic and mixed episodes and as maintenance therapy for people affected by bipolar disorder. Based on MEDLINE citations up to November 2010 and hand-searched references, this article relating to ziprasidone addresses its short- and long-term efficacy and safety, according to the results of randomized clinical trials, open-label studies and real-world experiences. Emerging evidence indicates that in patients with bipolar disorder, ziprasidone provides valid efficacy and remarkable safety when administered alone for the treatment of manic and mixed episodes. The same applies when ziprasidone is administered in combination with lithium or valproate for the prevention of affective relapses and recurrences. Any conclusion on the potential of ziprasidone as an antidepressant should be postponed because of insufficient evidence.