Overall, NSD family can reshape the epigenetic and transcriptional landscapes of tumor cells in both H3K36 methylation-dependent and –independent manners, thereby contributing to various malignant phenotypes, including tumorigenesis, cancer cell proliferation, epithelial–mesenchymal transition (EMT), invasion and metastasis, as well as therapeutic response, highlighting NSD1, NSD2, and NSD3 as promising epigenetic therapeutic targets. The gene discussed is NSD2; the disease is cancer.