The methylation of proteins at lysine residues has important regulatory roles. However this process is not well understood, because for many known protein lysine methylation sites, the responsible enzyme is not known and, vice versa, for many methylation enzymes only one or few substrates have been identified. In a new publication in J. Mol. Biol., we investigate the peptide recognition of the SUV4-20H1 and SUV4-20H2 protein lysine methyltransferases, which methylate histone H4 at lysine 20 –an essential modification in human cells. We determined the substrate specificity profile of both enzymes and based on this, we identified novel substrate proteins, which have already been demonstrated to be methylated in human cells. Our data show that the specificity of both SUV4-20 enzymes is different, suggesting overlapping but also distinct biological roles of both enzymes, which can explain the presence of the two very similar enzymes in the human genome. Finally, we show that the previously reported methylation of EKR1 by SUV4-20H1 is not detectable and discuss the possible reasons and consequences of this finding.