Protein arginine methyltransferases 5 (PRMT5), a therapeutic target whose main physiological function is mono- and symmetric dimethylation of arginine, has drawn significant attention from researchers in the field. PRMT5 has been reported to participate in many cellular functions including cell growth, migration, and development. Upregulation of PRMT5 occurs in different kinds of tumors and is strongly associated with poor prognosis. In recent years, several PRMT5 inhibitors have entered clinical trials for the treatment of various cancers, such as advanced or recurrent solid tumors with MTAP deletion. Herein, we reviewed the binding modes and structure-activity relationships of novel PRMT5 inhibitors and discussed prospects of PRMT5 inhibitors in cancer therapy, aiming to provide insights on drug development of PRMT5 inhibitors.