Exciting new clinical and preclinical studies suggest that activators of M1 and/or M4 subtypes of muscarinic acetylcholine receptors (mAChRs) could provide a novel approach for improving psychotic symptoms, as well as cognitive deficits and negative symptoms in patients suffering from schizophrenia. However, a lack of highly selective molecular and genetic probes for each of the individual mAChR subtypes have made it difficult to understand the roles of these two mAChR subtypes in modulating brain circuits and symptom domains that are relevant for schizophrenia. Also, non-selective mAChR agonists suffer from adverse effects due to activation of peripheral mAChR subtypes. We discovered and advanced highly selective positive allosteric modulators (PAMs) for M1 and M4 receptors. Use of these new molecular probes, along with genetic mouse models that allow us to selectively manipulate M1 and M4 signaling in specific brain circuits, are allowing us to make unprecedented advances in our understanding of the specific roles of each receptor in brain circuits that are relevant for schizophrenia, and highly optimized M1 and M4 PAMs are now advancing to clinical testing for potential efficacy in treatment of different symptom domains in schizophrenia patients.