Protecting against ionizing radiation is a critical challenge in medicine and radiobiology due to the increasing use of radiotherapy in oncology and the risk of radiation accidents. The development of effective and safe radioprotective agents remains associated with significant problems and limitations. The paper explores recent data on radioprotectors (preventive agents) and radiomitigators (agents that mitigate the effects of radiation), as well as current problems of their development and application. Classical synthetic aminothiols (amifostine) as well as modern strategies, including proinflammatory cytokine inhibitors (TGF-β), statins, ACE inhibitors, probiotics, and natural antioxidants, were analyzed. Fundamental limitations hindering widespread clinical use including a narrow therapeutic window, toxicity, and lack of selectivity toward healthy tissues during radiation therapy, have been identified. Although an ideal radioprotective drug has not been developed yet, modern research has advanced, shifting focus toward comprehensive radiation mitigation strategies to address delayed effects of radiation exposure.