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Background: Modulating the epigenome has long been considered a potential opportunity for therapeutic intervention in numerous disease areas with several approved therapies marketed, primarily for cancer. Despite the overall promise of early approaches, however, these drugs have been plagued by poor pharmacokinetic and safety/tolerability profiles due in large part to off-target effects and a lack of specificity., Results: Recently, there has been marked progress in the field on a new generation of epigenomic therapies which address these challenges directly by targeting defined loci with highly precise, durable, and tunable approaches. Here, we review the promise and pitfalls of epigenetic drug development to date and provide an outlook on recent advances and their promise for future therapeutic applications., Conclusions: Novel therapeutic modalities leveraging epigenetics and epigenomics with increased precision are well positioned to advance the field and treat patients across disease areas in the coming years., (© 2023. The Author(s).)