The authors have reviewed some of the most important and established factors that determine the effectiveness of IR in a wide variety of tumor types and normal tissues: the significance of increasing the dose of radiation, the importance of altered fractionation schemes, such as accelerated fractionation or hyperfractionation, and the need to address tumor hypoxia. Therapeutic gain can only be achieved when the increased tumor toxicity produced by these treatment modifications is balanced against injury to early-responding as well as late-responding normal tissues. In the not too distant future, therapeutic gain may be maximized by individualized therapies that are based on phenotypic and genotypic profiling of tumors and patients. For example, predicting which tumors respond to IR with accelerated tumor cell repopulation will allow us to apply more intense accelerated treatment regimens, while subjecting patients with slowly proliferating tumors to less toxic therapies. Similarly, the combination of radiation therapy with molecularly targeted pharmacologic agents will be a highly individualized treatment approach. However, to some degree, radiation therapy will always have to remain unselective and indiscriminant to inactivate the last surviving dormant and probably drug-resistant tumor clonogen. Although the field of radiation biology is rapidly evolving as a result of advances in molecular biology and genetics and the availability of new technologies, a thorough understanding of the established factors that determine radiation responses will remain an important prerequisite for the successful application of multimodal cancer therapies and molecularly targeted approaches in the future.