The disruption of genomic DNA methylation patterns was the first epigeneticabnormality to be described in human cancer. This imbalance involves thepromoter CpG island hypermethylation of tumor-suppressor genes, causingtranscriptional repression, and global genomic hypomethylation, leading tochromosomal instability and reactivation of endoparasitic sequences. Therelationship between DNA methylation and histone modifications was initiallydescribed in the context of the inactivation of female X chromosomes and of thedemonstration of strong interactions between the DNA methylation machinery andchromatin modifiers. The repression of tumor-suppressor genes by promoterhypermethylation was also found to be associated with a specific histonemodification index. However, this jigsaw was missing a piece: a global view of howthe histone modification landscape was distorted in cancer cells. We have recentlydiscovered this piece of the puzzle, demonstrating that the association betweenDNA methylation and histone modification aberrations in cancer also occurs at theglobal level. In human and mouse tumors, histone H4 undergoes a loss ofmonoacetylated and trimethylated lysines 16 and 20, respectively. Mostimportantly, these alterations occur within the context of the repetitive DNAsequences that also become hypomethylated in transformed cells. The globalalterations of histone acetylation status suggest novel pathways by which histoneacetyltransferases (HATs), histone methyltransferases (HMTs), and histonedeacetylases (HDACs) may play roles as tumor-suppressor genes or oncogenes. Inthis regard, we have shown how the generation of particular fusion proteinsinvolving HATs in leukemias is associated with an erasure of the monoacetylatedlysine 16-H4 marker, whilst the loss of trimethylation at lysine 20-H4 disruptsheterochromatic domains and may reduce the response to DNA damage of cancercells.