Antipsychotic polytherapy (APT) has evolved as a common treatment strategy at odds with recommendations from schizophrenia treatment guidelines. The literature on combinations with clozapine as a means to enhance efficacy and with aripiprazole to reduce side effects was reviewed. No solid evidence supporting antipsychotic combinations with clozapine for treatment-resistant patients with schizophrenia was identified. The reason for this may be that most combinations with clozapine increase the D(2)-receptor blockade, and this strategy is probably not efficient for patients with treatment-resistant schizophrenia. Some basic and clinical evidence for the addition of aripiprazole to lower prolactin levels was identified. In conclusion, there is very limited support in the evidence for the feasibility of rational APT.