Despite good achievements in prevention and control, cancer is still a leading cause of death worldwide. The development of resistances against conventional treatment modalities is one of the main causes of failure in the treatment of cancer. Radio- and chemotherapies fail frequently due to intrinsic or acquired resistances in apoptotic signalling pathways or alterations in DNA-repair processes. Targeted radiotherapies employing α-particle-emitting radionuclides and Auger-emitting electrons are a promising approach in cancer treatment to break radio- and chemoresistance by overcoming DNA-repair mechanisms and reversing deficient activation of apoptotic pathways in cancer cells.