SET and MYND domain-containing (SMYD) proteins constitute an evolutionarily conserved subfamily of lysine methyltransferases, characterized by a catalytic SET domain split by a MYND domain.7,8 Among them, SMYD5 was recently reported to catalyze methylation of viral Tat protein and be involved in HIV infection,9 as well as to catalyze histone H3K36me3 at promoters and drive tumorigenesis in hepatocellular carcinoma (HCC),10 though the downstream mechanism is unclear. The gene discussed is SMYD5; the disease is hepatocellular carcinoma.