Radiosensitivity (RS) is a key determinant of radiotherapy (RT) efficacy, influencing how cancer cells respond to ionizing radiation. This response is governed by a complex interplay of biological mechanisms that regulate oxidative stress mitigation, repair mechanisms, and cell death evasion. This chapter explores the key factors contributing to intrinsic RS, the fifth “R” of radiobiology. To enhance their survival following radiation exposure, cancer cells upregulate antioxidant systems, which neutralize radiation-induced reactive oxygen species. Additionally, mitochondrial adaptations contribute to maintain redox homeostasis and promote radioresistance. Cancer cells also exploit DNA repair pathways, enabling efficient recovery from radiation-induced DNA damage. Beyond various repair mechanisms, cancerous cells prevent the apoptosis process through upregulating anti-apoptotic mediators and suppressing death-inducing signaling complex formation. Furthermore, resistance to other regulated cellular death pathways, such as pyroptosis, necroptosis, and ferroptosis, enhances tumor survival after RT. In addition, senescence induction can impair radiation response by creating an immunosuppressive tumor microenvironment that hinders antitumor immune activity. A deeper understanding of these resistance mechanisms is required for designing targeted therapeutics to enhance RT efficacy and clinical outcomes in radioresistant cancers.