Posttranslational modifications of histones are critical to the regulation of DNA-directed activities. Histone modifications include acetylation, sumoylation, phosphorylation, ubiquitination, and methylation (1). Histone lysine methylation serves as critical mark for the recruitment of specific factors for chromatin remodeling and the regulation of replication, repair, recombination, transcription, and RNA processing. The methylation of histone H3 occurs on five lysine residues (K4, K9, K27, K36 and K79) (1;2). H3K4 (histone H3, lysine 4)methylation is associated exclusively with actively transcribed genes and exists in a mono-, di- and tri-methylated form. The yeast COMPASS/Set1 complex was the first H3K4 methyltransferase complex identified and is composed of eight subunits. The yeast Set1 complex is strongly conserved in humans and shown to be nearly identical to the human Set1 complex (hSet1).  In yeast, the COMPASS/Set1 complex is the only H3K4 methylase present; however in mammals, 6 homologs of Set1 have been identified: hSet1A, hSet1B, MLL1, MLL2, MLL3, and MLL4. These subunits exist in at least 4 distinct complexes: hSet1 complex, MLL complex, MLL2 complex, and MLL3/4 complex.  Each complex contains distinct subunits as well as shared subunits (2;3).  The yeast model has provided a wealth of information on the mechanism of H3K4 methylation, further studies of the homologous mammalian complexes will yield clues on the specific roles that histone modifications play in the regulation of gene expression.