Abstract: The methylation of lysine residues in the N-terminal tails of histones is a highly conserved mechanism that regulates critical functions of chromatin, such as the control of gene expression. Using a biochemical approach, we recently identified new methylation marks on the histone H4 tail in budding yeast at lysines 5, 8 and 12, catalyzed by the previously-uncharacterized enzyme Set5. Genetic studies revealed that Set5 functions in cellular processes that also rely on the global chromatin modifying complexes COMPASS and NuA4, which methylate H3 lysine 4 and acetylate H4 lysines 5, 8 and 12, respectively. The identification of new methylation events on the H4 tail raises many intriguing questions regarding their function and their interaction with known histone modifications. Here, we analyze the insights gained about the new enzyme Set5 and the implications for new functionality added to the H4 tail.