The article reviews the role of Lys36 (H3K36) methylation on histone H3 in various biological processes and its implications in human diseases. H3K36 methylation is primarily associated with active euchromatin but also plays roles in transcriptional repression, alternative splicing, dosage compensation, DNA repair, and recombination. The methylation of H3K36 is catalyzed by specific methyltransferases, including Set2 and NSD1, which have distinct substrate specificities and regulatory mechanisms. The article discusses the regulation of H3K36 methylation by cofactors and the involvement of this modification in gene expression, dosage compensation, transcriptional initiation, repression, exon definition, DNA replication, and repair. Additionally, it highlights the links between H3K36 methylation and several diseases, including cancer, where defects in the enzymes responsible for maintaining H3K36 methylation patterns can lead to developmental defects and cancer development. The authors emphasize the complexity of the combinatorial histone language and the need to understand the distinct complexes formed by these enzymes in different cell types and developmental stages.The article reviews the role of Lys36 (H3K36) methylation on histone H3 in various biological processes and its implications in human diseases. H3K36 methylation is primarily associated with active euchromatin but also plays roles in transcriptional repression, alternative splicing, dosage compensation, DNA repair, and recombination. The methylation of H3K36 is catalyzed by specific methyltransferases, including Set2 and NSD1, which have distinct substrate specificities and regulatory mechanisms. The article discusses the regulation of H3K36 methylation by cofactors and the involvement of this modification in gene expression, dosage compensation, transcriptional initiation, repression, exon definition, DNA replication, and repair. Additionally, it highlights the links between H3K36 methylation and several diseases, including cancer, where defects in the enzymes responsible for maintaining H3K36 methylation patterns can lead to developmental defects and cancer development. The authors emphasize the complexity of the combinatorial histone language and the need to understand the distinct complexes formed by these enzymes in different cell types and developmental stages.