The ability of eukaryotes to alter chromatin structure and function is modulated, in part, by histone-modifying enzymes and the post-translational modifications they create. One of these enzymes, PR-Set7/Set8/KMT5a, is the sole histone methyltransferase responsible for the monomethylation of histone H4 lysine 20 (H4K20me1) in higher eukaryotes. Both PR-Set7 and H4K20me1 were previously found to be tightly cell cycle regulated suggesting that they play an important, although unknown, role in cell cycle progression. Several recent reports reveal that PR-Set7 abundance is dynamically regulated during different cell cycle phases by distinct enzymes including cdk1/cyclinB, Cdc14, SCF(Skp2), CRL4(cdt2) and APC(cdh1). Importantly, these reports demonstrate that inappropriate levels of PR-Set7 result in profound cell cycle defects including the inability to initiate S phase, the re-replication of DNA and the improper timing of mitotic progression. Here, we summarize the significance of these new findings, raise some important questions that require further investigation and explore several possibilities of how PR-Set7 and methylated H4K20 may likely function as novel regulators of the cell cycle.