Purpose/Objective(s): Radioresistance limits the efficacy of radiotherapy, but the epigenetic determinants of this process remain poorly understood. Our objective was to screen pan-cancer epigenetic regulators associated with radiosensitivity and radioresistance. Materials/Methods: Epigenetic Crispr screening was combined with second-generation sequence technology to identify epigenetic regulators of radiosensitivity and radioresistance. We performed epigenetic CRISPRCas9 screens in murnie cell lines Hepa1-6 (hepatic carcinoma), LLC1 (lung adenocarcinoma) and MC38 (colon carcinoma) to systematically discover epigenetic regulators of radioresistance through cell proliferation assay and colony formation assay. The functions of identified genes were further validated in radioresistant cells lines.