The Search for Therapeutic Gain in Radiation Oncology Novel strategies in radiation oncology aim at increasing the therapeutic gain, i.e., to decrease side effects while maintaining cure rates, or to increase cure rates at the same level of complications. Over the years, physical and biological strategies have been developed to achieve this goal. The physical development led to the possibility of precise, computer-controlled beam application by using modern imaging techniques and three-dimensional treatment planning. Improved patient immobilization methods allow minimal safety distances, resulting in steep dose gradients when used together with isocentric multi-field techniques. These predominantly stereotactic irradiation techniques yield therapeutic gain towards the tumor surrounding normal tissue. A critical issue that determines the tolerance of radiation therapy are structures at risk within the target volume. Fractionation is a reliable method to exploit the differential potential for recovery of radiation-induced DNA damage in normal tissues. Radiogenetic strategies aim at the sensibilization of tumor cells by targeting specific characteristics like mutations of p53. The reverse idea, gene-therapeutic radioprotection of normal tissue, is under investigation.