Modulation of muscarinic acetylcholine receptors (mAChRs) is one of the most attractive therapeutic strategies for the treatment of schizophrenia. Pilot clinical studies of the M1/M4 mAChR-preferring agonist xanomeline as well as animal studies using M1–M5 mAChR knockout mice suggest that selective activation of M1 and/or M4 mAChRs is a key concept in the treatment of psychosis and cognitive deficits in patients with schizophrenia. However, over the past two decades, clinical development of mAChR agonists has not been successful mainly due to these agents’ narrow safety margin caused by the lack of true subtype selectivity. However, recent advances in medicinal chemistry might enable researchers to overcome the hurdles that earlier mAChR agonists failed to pass. Here, we describe recent advances in the development of subtype-selective mAChR activators for treatment of schizophrenia.