Posttranslational modifications of proteins critically regulate the function, localization, and stability of target proteins. Histone modification is one of the regulatory mechanisms that modulate the chromatin structure and thereby affect various DNA-templated processes, such as gene transcription, DNA replication, DNA recombination, and DNA repair in cells. These molecular processes contribute to basic cellular functions, including cell cycle, cell growth, and apoptosis. Histone modifications consist of acetylation, methylation, phosphorylation, ubiquitination, sumoylation biotination, citrullination, poly-ADPribosylation, and N-glycosylation. The modification status of histone is balanced by two enzyme families with opposing catalytic activities: histone modifying and de-modifying enzymes. Recent studies have shown that dysfunction of histone modification enzymes is a major cause for human cancer initiation and progression. In this review, we will summarize the functions of histone modification enzymes in cancer, and the mechanisms that histone modification enzymes use to drive or suppress human malignancies.