Introduction: Antipsychotic polypharmacy (APP), defined as the use of more than one antipsychotic, is common in schizophrenia. However, current guidelines consider that the level of evidence to support APP is weak and mostly recommend monotherapy. Areas covered: Meta-analyses of randomized controlled trials (RCTs) on the efficacy and tolerability of APP, effectiveness studies on its use in clinical practice, as well as theoretical models liable to legitimate this use are reviewed and discussed on the basis of a systematic literature search (PubMed) ranging from 1995 to 2020. Expert opinion: There is now increasing evidence from both efficacy and effectiveness studies, that APP may be beneficial for some schizophrenia patients. The most evidence seems to be for the combination of clozapine and aripiprazole. The choice of this combination may fit in well with the dopamine supersensitivity hypothesis in schizophrenia. Guidelines should be revised, but further studies are needed to confirm the efficacy/effectiveness of this combination, especially in the case of first-episode schizophrenia.