Antipsychotic monotherapy is strongly recommended in the treatment of schizophrenia. However, antipsychotic polypharmacy (APP) is common in clinical practice, and appears to be related to illness severity and duration, treatment-refractoriness, hospitalization status, duration of hospitalization, geographic region and age. Given the high number of different antipsychotic combinations reported in the literature and prescribed in clinical practice, there are perhaps more differences than similarities between such combinations. While the majority of combinations increase side-effect burden, limited evidence suggests benefits of certain combinations.Until more data are available, APP should be reserved for difficult-to treat patients, with careful consideration of pharmacodynamics properties and doses of each drug, as well as close monitoring.