Protein arginine methyltransferase 5 (PRMT5) is the primary type II methyltransferase that mainly catalyzes symmetric demethylation of arginine residues in both histone and nonhistone proteins. Increasing evidence has demonstrated that PRMT5 is indispensable in tumorigenesis and acquired therapeutic resistance in multiple malignancies. This review summarizes the clinical significance of PRMT5 in solid tumors such as lung cancer, breast cancer, and glioblastoma, its role in tumor immunology, and current clinical trials of PRMT5 inhibitors, and discusses the clinical status, current dilemma, and future perspectives of PRMT5 inhibition as a novel therapeutic strategy.