Histone methylation is a type of epigenetic modification that is critical for the regulation of gene expression. Numerous studies have demonstrated that abnormalities of this newly characterized epigenetic modification are involved in the development of multiple diseases, including cancer. There is also emerging evidence for a link between histone methylation and the pathogenesis of myeloid neoplasms, including myelodysplastic syndromes (MDS). This article provides an overview of recent progress in the studies of histone methylation in myeloid malignancies, with an emphasis on MDS. We cover each type of histone methylation modification and their regulatory mechanisms, as well as their abnormalities in MDS or potential connections to MDS. We also summarize the recent progress in the development of inhibitors targeting histone methylation and their applications as potential therapeutic agents.