Epigenetic changes including DNA methylation, histone modifications, chromatin remodeling and microRNAs play critical roles in tumorigenesis and tumor development. Reversal of epigenetic changes sensitizes some tumor cells to radiation. DNMT-I enhances the response of tumor cells to radiotherapy. AZA demethylated promoters of genes related to ionizing radiation response, such as p16 and hMLH1. The genes expression of the p53, RASSF1, and DAPK gene families was increased by 5-aza-CdR, which induces G2-M phase arrest and increased apoptosis. HDAC-I has both anti-tumor activity and radiation sensitization activity. HDAC-I disrupts both DNA damage sensing and repair processes: HDAC-I disrupts the association between HDAC enzyme and DNA sensor proteins 53BP1 and ATM. HDAC-I changes the acetylation status of both proteins involved in homologous recombination (HR) repair pathway which include BRCA1, Rad51, and Rad50, and proteins involved in non-homologous end joining (NHEJ) repair pathway which include Ku70, and DNA-PK. HDACs are also implicated as essential components in the DNA repair process itself. Besides the radiosensitizing mechanism of intervention of DNA repair, other possible mechanisms including cell cycle redistribution, acetylation of Hsp90, increased apoptosis, and decreased survival signals are also suggested. Some miRNAs also regulate the radiosensitivity of tumor cells. Inhibition of miR-34 expression or function, downregulation of miR-155, upregulation of miR-18a, Overexpression let-7g or knocking down LIN28B, and ectopically overexpressed miR-10 in cells with low endogenous miR-101 level increase the response of cells to irradiation. For radiation-resistant cancer cells, miR-7 sensitizes the radiation for cells which activated EGFR-PI3K-AKT signaling pathway.