Histone-modifying enzymes have recently been shown to play a central role in the regulation of both normal and malignant hematopoiesis. Post-translational modifications of histones and non-histone proteins underlies a regulatory complexity affecting numerous processes including transcriptional regulation, RNA processing and DNA damage response. Insights into the functions of these enzymes as well as their role in the epigenetic alterations found in leukemia will guide the development of novel therapeutic approaches. This review discusses examples of the proteins that have been implicated in the pathogenesis of leukemia, that may serve as potential therapeutic targets.