Concurrent administration of radiation and chemotherapy has emerged as a dominant form of cancer treatment. Nevertheless, our understanding of the specific mechanisms of interaction between radiation and chemotherapy is still evolving. Biological evidence gained in experimental cell lines and tumors suggests that cisplatin lesions cause repair inhibition of radiation-induced DNA damage affecting both homologous recombination and nonhomologous end joining. In the case of 5-fluorouracil (5-FU), the crucial event in the radiosensitisation process appears to be inappropriate progression through S-phase in the presence of bound drug affecting both DNA repair and cell cycle. In similar fashion, data with gemcitabine suggest that radiosensitization arises through progression into S-phase causing depletion of 2'-deoxyadenosine 5'-triphosphate pools, which leads to misincorporation and misrepair of incorrect bases in irradiated cells. As the new molecular-targeted agents become increasingly available to complement established radiation and chemoradiation treatment regimens, new concepts of drug-radiation interaction are evolving that require innovative thinking regarding the manner in which radiation and drugs cooperate and how clinical trials are best performed.