<p>Until very recently, every drug approved for the treatment of schizophrenia over the past 70 years had the primary mechanism of directly or indirectly antagonizing dopamine D₂ receptor activation. The role of dopamine as a critical mediator of psychosis is well established, and psychotic symptoms such as hallucinations and delusions are key features of schizophrenia. However, other important symptoms, including negative symptoms such as social withdrawal and anhedonia, and cognitive impairments, are largely unaffected by current antipsychotic drugs, resulting in the persistent disability of most individuals with schizophrenia. Schizophrenia also results in premature death due to a high prevalence of cardiovascular disease that can be exacerbated by current antipsychotic medications. Advances in our understanding of the genetics and pathophysiology of schizophrenia demonstrate that the disorder is complex with numerous underlying aetiologies, indicating that a single drug is unlikely to affect all aspects of the disorder. The recent approval of the M₁/M₄ muscarinic acetylcholine receptor agonist xanomeline/trospium chloride has begun to expand the therapeutic toolbox for schizophrenia. This Review covers promising drug targets for schizophrenia treatment that impact neurotransmitter systems, immune processes and inflammation. Despite failed clinical trials of some agents with novel mechanisms, several have recently been shown to improve one or more symptom domains of schizophrenia, suggesting that these targets may lead to more effective treatments.</p>