Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins, protein methylation plays important regulatory roles in gene expression, protein activity and stability, and signal transduction. Methylation can occur on specific lysine or arginine residues localized within regulatory domains in both histone and nonhistone proteins, thereby allowing distinguished properties of the targeted protein. Lysine can be methylated to different degrees, including mono-, di-, or trimethylation, which reflects its functional diversity and regulatory complexity compared to other PTMs. Lys9 of histone H3 is mono- or di-methylated by G9A/GLP and tri-methylated by SETDB1 to activate transcription. Tumor suppressor p53 is regulated by methylation of at least four sites. p53-mediated transcription is repressed following mono-methylation of p53 at Lys370 by SMYD2; Di-methylation at the same residue further inhibits p53 by preventing association with 53BP1. Concomitant di-methylation at Lys382 inhibits p53 ubiquitination following DNA damage. Di-methylation at Lys373 by G9A/GLP inhibits p53-mediated apoptosis and correlates with tri-methylation of histone H3 Lys9 at the p21 promoter.