Radiotherapy (RT) is one of the mainstay treatments for prostate cancer (PCa), a highly prevalent neoplasm among males worldwide. About 30% of newly diagnosed PCa patients receive RT with a curative intent. However, biochemical relapse occurs in 20-40% of advanced PCa treated with RT either alone or in combination with adjuvant-hormonal therapy. Epigenetic alterations, frequently associated with molecular variations in PCa, contribute to the acquisition of a radioresistant phenotype. Increased DNA damage repair and cell cycle deregulation decreases radio-response in PCa patients. Moreover, the interplay between epigenome and cell growth pathways is extensively described in published literature. Importantly, as the clinical pattern of PCa ranges from an indolent tumor to an aggressive disease, discovering specific targetable epigenetic molecules able to overcome and predict PCa radioresistance is urgently needed. Currently, histone-deacetylase and DNA-methyltransferase inhibitors are the most studied classes of chromatin-modifying drugs (so-called 'epidrugs') within cancer radiosensitization context. Nonetheless, the lack of reliable validation trials is a foremost drawback. This review summarizes the major epigenetically induced changes in radioresistant-like PCa cells and describes recently reported targeted epigenetic therapies in pre-clinical and clinical settings.