Epigenetics refers to heritable changes that are not encoded in the DNA sequence. It has emerged that histones, the basic building blocks of the hierarchical chromatin structure in eukaryotes, are major carriers of epigenetic information. The evolutionarily conserved covalent modifications such as histone methylation play important roles in chromatin-template based processes including transcrition, replication and DNA damge repair. Mutations in histone methyltransferases are frequently found in human malignancies. Our research focuses on MLL family histone methyltransferases ant their roles in cell fate determination during physiological and maligant proceses. Using combined bioichemistry, genetic and chemical biology approaches, we have uncovered novel mechanisms by which MLL function in cells and establish MLL as a potential therapeutic target in leukemia.