Cancer is still a major worldwide health concern, even with improvements in treatment approaches. The widespread use of radiotherapy, a well-established cytotoxic approach for many malignancies, has notably improved survival rates for patients. Traditionally, radiation is recognized for its ability to directly alter the DNA double helix structure, initiating DNA damage responses that can lead to necrosis, apoptosis, or cellular senescence. These processes can disrupt normal mitotic functions and ultimately modify the biological properties of cancer cells. According to recent research, radiation has a major impact on the immunogenicity, phenotypic, and surrounding tumor microenvironment of cancerous cells, leading to broader and more complex changes in cancer cell biology. It is noteworthy that some cancer cells can evade programmed cell death through the overactivation of pathways for DNA repair in the event of genomic damage. Furthermore, these surviving cells exposed to radiation often exhibit modification of the expression of significant oncogenes and tumor suppressor genes. This alteration can enhance various hallmarks of cancer, such as invasion, migration, and metastasis. Together with other epigenetic and structural cellular alterations, the induction of these genetic processes results in the phenomenon known as tumor radioresistance and is influenced by external factors from the tumor microenvironment. Understanding the intricate molecular and cellular mechanisms behind radioresistance is necessary, as it might unveil novel treatment objectives as well as diagnostic markers. This knowledge may ultimately contribute to improving radiation therapy (RT) outcomes through the establishment of novel therapeutic approaches, including the use of radiosensitizers and targeted approaches. This chapter discusses the mechanisms by which radiation affects cancer cells, the development of radioresistance, and potential therapeutic methods to improve RT’s effectiveness.