Combination therapy is well established in bipolar disorder; however, the evidence for this approach in schizophrenia is less robust. Despite the absence of clear guidance, antipsychotic combinations are commonly used in real-life practice, with estimates suggesting that 20–60% of patients receive multiple antipsychotics concurrently. Such polypharmacy may be clinically useful, combining diverse pharmacological actions. However, a clear pharmacological rationale for specific antipsychotic combinations has not yet been elucidated. In this presentation, we consider the varying pharmacological profiles of agents currently used for schizophrenia and explore how best this pharmacology may be exploited to maximize the newer atypicals in clinical practice. For decades schizophrenia has been treated with some success using typical antipsychotics, which are antagonists at dopamine D2 receptors. Atypical antipsychotics were then developed, having D2 antagonism with additional affinity for other receptors, such as serotonin 5-HT2A and 5-HT1A receptors. Most recently, partial D2 agonists have been developed with efficacy to treat schizophrenia and bipolar disorder. These agents have lower intrinsic activity than full agonists, so can act either as functional agonists or antagonists. Additionally, actions to increase noradrenergic function in the prefrontal cortex may be implicated in the efficacy of some antipsychotics. Given the rich pharmacology of antipsychotics, can the combined use of agents with synergistic mechanisms of action provide a true clinical advance in schizophrenia treatment? Polypharmacy is a complex challenge that requires further study in well-designed, randomized, controlled studies. We will review the pharmacological rational for antipsychotic combination therapy and recent clinical evidence for their benefits.