Among the muscarinic acetylcholine receptor (mAChR) subtypes, the M₄ receptor has been investigated as a promising drug target for the treatment of schizophrenia. These investigations have been based on findings from M₄-deficient mice studies as well as on the results of a clinical trial that used xanomeline, an M₁/M₄ mAChRs-preferring agonist. Both orthosteric agonists and positive allosteric modulators of M₄ mAChR have been reported as promising ligands that not only have antipsychotic effects, but can also improve cognitive impairment and motor dysfunction. However, challenges remain due to the high homology of the orthosteric binding site among all muscarinic receptors. In this review, we summarize our approach to the identification of M₄ mAChR activators, orthosteric agonists, and positive allosteric modulators based on M₄ mAChR structural information and structure–activity relationship studies. These findings indicate that selective M₄ mAChR activators are promising potential therapeutic agents for several central nervous system conditions.