Persistent increases in the incidence and mortality rates of biliary tract cancers implicate this heterogeneous group of malignancies as a growing threat to population health worldwide. The failure of current chemotherapy to extend median survival beyond one year highlights the extensive innate and rapidly acquired chemoresistance of these tumors, although the underlying molecular mechanisms remain opaque. Notably, a significant proportion of the mutational landscape in cholangiocarcinoma (CCA) comprises recurrent mutations in epigenetic regulators, implying extensive (epi)genome-wide consequences arising from mutant isoform activities. These findings suggest CCA may be a prime solid tumor candidate for epigenome-targeted therapies. In this chapter we assess the epigenomic architecture of CCA and subsequent indications for patient stratification and personalization of epigenetic therapy. From this we contextualize epigenetic therapies into different prospective clinical applications (including differentiation therapy, immune modulation, and chemosensitization). Finally, we discuss the challenges that must be overcome in future CCA epigenomics studies to improve the translation of research (basic and translational) findings into the clinic.