Histone post-translational modification is a key step that may result in an epigenetic mark that regulates chromatin structure and gene transcriptional activity thereby impacting many fundamental aspects of human biology. Subtypes of post-translational modification such as acetylation and methylation are executed by a variety of distinct modification enzymes. The cytoplasmic and nuclear concentrations of these enzymes are dynamically and tightly controlled at the protein level to precisely fine-tune transcriptional activity in response to environmental clues and during pathophysiological states. Recent data have emerged demonstrating that the life span of these critical nuclear enzymes involved in histone modification that impact chromatin structure and gene expression are controlled at the level of protein turnover by ubiquitin–proteasomal processing. This review focuses on the recent progress on mechanisms for ubiquitin–proteasomal degradation of histone modification enzymes and the potential pathophysiological significance of this process.