The efficacy of radiation is further improved by use of various agents which sensitize the cells to radiation, thereby boosting the mortality rate sustained by radiation. To develop clinically relevant radiosensitizers requires an approach combining radiation with standard cytotoxic chemotherapeutic agents. However, even this becomes a risky set-up owing to the fact that these chemotherapeutic agents have their own set of side effects which needs to be counteredChemointervention has emerged lately as a novel approach in both preventing the disease as well as to increase the efficiency of the treatment modules presently in use. Naturally occurring compounds like curcumin, parthenolide, genistein, gossypol, ellagic acid, withaferin, plumbagin, etc., which are generally safe for normal cells, are known to possess anticancer properties and have been studied to show synergistic effect along with radio- and chemotherapy, in addition to showing protection to normal tissues. We focus on current theories regarding the molecular mechanisms mediating radiation resistance and the chemomodulatory effects of phytochemicals in ionization radiation-mediated cancer therapy.