In epigenetic research, the abnormality of protein methylation modification is closely related to the occurrence and development of tumors, which stimulates the interest of researchers in protein methyltransferase research and the efforts to develop corresponding specific small molecule inhibitors. Currently, the protein lysine methyltransferase SMYD2 has been identified as a promising new small molecule target for cancer therapy. But its biological functions have not been fully studied and relatively few inhibitors have been reported, thus this field needs to be further explored. This perspective provides a comprehensive and systematic review of the available resources in this field, including its research status, biological structure, related substrates and methylation mechanisms, and research status of inhibitors. In addition, this perspective elaborates in detail the current challenges in this field, our insights into what needs to be done next, rational drug design of novel SMYD2 inhibitors, and foreseeable development directions in the future.