Histones H3 and H4 are the predominant histones modified by methylation and are highly methylated in mammalian cells. Lysine residues can be mono-, di-, and tri-methylated, adding further complexity to the regulation of chromatin structure. Conserved lysine residues in the N-terminal tail domains of histone H3, Lys-4, Lys-9 and Lys-27 are the preferred sites of methylation. Methylation of H3 at Lys-9 is a modification intrinsically linked to epigenetic silencing and heterochromatin assembly. Histone H3 is methylated at Lys-9 by site-specific H3 methyltransferases (HMTases) and generates a binding site for heterochromatin protein 1 (HP1).