SMYD3(SET and MYND domain-containing 3) is a histone methyltransferase which functions in RNA polymerase II complexes by an interaction with a specific RNA helicase. SMYD3 is responsible for the methylation of Lys-4 on Histone H3, a modification that serves as a specific marker for epigenetic transcriptional activation, thereby influencing gene expression patterns essential for cellular function and development. SMYD3 features an N-terminal MYND-type zinc finger domain followed by a SET domain, which is integral to methyltransferase activity. Additionally, the presence of heat shock protein HSP 90A significantly enhances SMYD3 methyltransferase activity, highlighting the importance of protein interactions in regulating function. SMYD3 is predominantly expressed in testis and skeletal muscle tissues and is found to be over-expressed in a majority of colorectal carcinomas, hepatocellular carcinomas, and breast carcinomas, making SMYD3 a potential target for therapeutic intervention in cancer treatment.