The methylation of histones plays a pivotal role in the regulation of chromatin structure and gene expression. Histone methylation can occur on Arg or Lys residues, with an exquisite site selectivity for Lys methylation at specific positions in the N-termini of histones H3 and H4. SET7/9, a histone methyltransferase (HMTase), which transfers methyl groups to Lys4 of histone H3, forms a complex with S-adenosyl-L-methionine. This complex contains an active site consisting of a binding pocket where an AdoMet molecule in an unusual conformation binds, a narrow substrate-specific channel that only unmethylated lysine residues can access and a catalytic tyrosine residue.