The molecular biology of histone H4 lysine 20 (H4K20) methylation, like many other post-translational modifications of histones, has been the subject of intensive interest in recent years. While there is an emerging consensus linking H4K20me1, H4K20me2, and H4K20me3 to transcription, repair, and constitutive heterochromatin, respectively, the specific details of these associations and the biological mechanisms by which the methylated histones are introduced and function are now the subject of active investigation. Although a large number of methylases capable of methylating H4K20 have been identified and characterized; there is no known demethylase of H4K20, though the search is ongoing. Additionally, many recent studies have been directed at understanding the role of methylated H4K20 and other histone modifications associated with different biological processes in the context of a combinatorial histone code. It seems likely that continued study of the methylation of H4K20 will yield extremely valuable insights concerning the regulation of histone modifications before and during cell division and the impact of these modifications on subsequent gene expression.