The current review gives a brief account of the DNA damage response pathway and involvement of various epigenetic mechanisms in DNA damage response pathway. The main focus is on histone modifications leading to structural alterations in chromatin since the compact chromatin structure poses a major limitation in the DNA repair process. Based on this hypothesis, our laboratory has also evaluated certain histone deacetylase inhibitors as potential radiomitigators and the same has been discussed in brief at the end of the review.