As a predominant type II protein arginine methyltransferase, PRMT5 plays critical roles in various normal cellular processes by catalyzing the mono- and symmetrical dimethylation of a wide range of histone and nonhistone substrates. Clinical studies have revealed that high expression of PRMT5 is observed in different solid tumors and hematological malignancies and is closely associated with cancer initiation and progression. Accordingly, PRMT5 is becoming a promising anticancer target and has received great attention in both the pharmaceutical industry and the academic community. In this Perspective, we comprehensively summarize recent advances in the development of first-generation PRMT5 enzymatic inhibitors and highlight novel strategies targeting PRMT5 in the past 5 years. We also discuss the challenges and opportunities of PRMT5 inhibition, with the aim of shedding light on future PRMT5 drug discovery.