Maintenance of genomic integrity is essential to ensure normal organismal 
development and to prevent diseases such as cancer. Nuclear DNA is packaged into 
chromatin, and thus genome maintenance can be influenced by distinct chromatin 
environments. In particular, post-translational modifications of histones have 
emerged as key regulators of genomic integrity. Intense research during the past 
few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically 
important for the biological processes that ensure genome integrity, such as DNA 
damage repair, DNA replication and chromatin compaction. The distinct H4K20 
methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation 
of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 
methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone 
methyltransferases leads to genomic instability, demonstrating the important 
functions of H4K20 methylation in genome maintenance. In this review, we explain 
molecular mechanisms underlying these defects and discuss novel ideas for 
furthering our understanding of genome maintenance in higher eukaryotes.