G9a, a histone lysine methyltransferase, is instrumental in regulating gene expression through epigenetic modifications. Its overexpression is closely linked to the progression of various human diseases, including cancers. Therefore, targeting G9a enzyme is a promising strategy for treating various diseases. Although no G9a inhibitors have yet reached clinical trials, several small molecule inhibitors have demonstrated strong preclinical efficacy. For instance, the orally available inhibitor 16 (DS79932728) shows significant potential for treating sickle cell disease, while 34 (compound 15h) has shown promising treatment of rhabdomyosarcoma. This Perspective summarizes the protein structure and biological functions of G9a, along with its association with various diseases. We highlight the design strategies, structure-activity relationships, and biological activity assessments of G9a inhibitors. Additionally, we discuss the unique advantages of the mechanisms of novel G9a inhibitors, offering insights for the future development of more effective drugs targeting G9a.