Site- and state-specific lysine methylation of histones is catalyzed by a family of proteins including those contain the evolutionarily conserved SET domain. Research on histone methyltransferases is a part of epigenetics, which plays a fundamental role in heterochromatin formation, X-chromosome inactivation and transcription regulation. Aberrant histone methylation was linked to a number of developmental disorders and human disease including several carcinomas. Histone lysine methylation is a functionally complex process, as it can either activate or repress transcription, depending on sequence-specific lysine methylation site in histones. Non-histone proteins were found to be methylated by SET domain-containing histone methyltransferases whose primary targets were presumed to be histones. The researches on histone methyltransferases will make a completely new space for transcriptional activity, embryonic development, cell differentiation, and signal transduction.