Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an integral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, cardiac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threatening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy.