Histone H3K36 methylation is a key modification that influences various cellular processes, including transcription, DNA repair, and chromatin structure. This review summarizes the current understanding of H3K36 methylation, focusing on the enzymes responsible for its modification, their regulation, and functional roles. Several enzymes, including SET domain-containing 2 (Set2) and nuclear receptor SET domain-containing 1 (NSD1), methylate H3K36. These enzymes have distinct preferences for different methylation states and interact with other chromatin components to regulate gene expression. NSD1 is a mono- and dimethylase for H3K36 and is involved in transcriptional regulation, DNA repair, and dosage compensation. NSD2 also methylates H3K36 and may act on H4K20 under certain conditions. Set2 is a trimethylase that couples H3K36me3 with transcriptional elongation. The methylation status of H3K36 can influence gene expression, DNA repair, and chromatin structure. Additionally, H3K36 methylation is involved in transcriptional repression, alternative splicing, and DNA replication. Defects in H3K36 methylation can lead to developmental disorders and cancer. The regulation of H3K36 methylation is complex and involves multiple enzymes and cofactors. Understanding the role of H3K36 methylation is crucial for elucidating the mechanisms of chromatin regulation and its impact on cellular processes.Histone H3K36 methylation is a key modification that influences various cellular processes, including transcription, DNA repair, and chromatin structure. This review summarizes the current understanding of H3K36 methylation, focusing on the enzymes responsible for its modification, their regulation, and functional roles. Several enzymes, including SET domain-containing 2 (Set2) and nuclear receptor SET domain-containing 1 (NSD1), methylate H3K36. These enzymes have distinct preferences for different methylation states and interact with other chromatin components to regulate gene expression. NSD1 is a mono- and dimethylase for H3K36 and is involved in transcriptional regulation, DNA repair, and dosage compensation. NSD2 also methylates H3K36 and may act on H4K20 under certain conditions. Set2 is a trimethylase that couples H3K36me3 with transcriptional elongation. The methylation status of H3K36 can influence gene expression, DNA repair, and chromatin structure. Additionally, H3K36 methylation is involved in transcriptional repression, alternative splicing, and DNA replication. Defects in H3K36 methylation can lead to developmental disorders and cancer. The regulation of H3K36 methylation is complex and involves multiple enzymes and cofactors. Understanding the role of H3K36 methylation is crucial for elucidating the mechanisms of chromatin regulation and its impact on cellular processes.