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The field is guided by biological principles active during development, wound healing, aging, and carcinogenesis. Skeletal development and tissue maintenance in adults represent highly intricate biological processes that require continuous adjustments in the expression of cell type\u2010specific genes that generate, remodel, and repair the skeletal extracellular matrix. Errors in these processes can facilitate musculoskeletal disease including cancers or injury. The fundamental molecular mechanisms by which cell type\u2010specific patterns in gene expression are established and retained during successive mitotic divisions require epigenetic control, which we review here. We focus on epigenetic regulatory proteins that control the mammalian epigenome at the level of chromatin with emphasis on proteins that are amenable to drug intervention to mitigate skeletal tissue degeneration (e.g., osteoarthritis and osteoporosis). We highlight recent findings on a number of druggable epigenetic regulators, including DNA methyltransferases (e.g., DNMT1, DNMT3A, and DNMT3B) and hydroxylases (e.g., TET1, TET2, and TET3), histone methyltransferases (e.g., EZH1, EZH2, and DOT1L) as well as histone deacetylases (e.g., HDAC3, HDAC4, and HDAC7) and histone acetyl readers (e.g., BRD4) in relation to the development of bone or cartilage regenerative drug therapies. We also review how histone mutations lead to epigenomic catastrophe and cause musculoskeletal tumors. The combined body of molecular and genetic studies focusing on epigenetic regulators indicates that these proteins are critical for normal skeletogenesis and viable candidate drug targets for short\u2010term local pharmacological strategies to mitigate musculoskeletal tissue degeneration. \u00a9 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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