Radiotherapy plays a crucial role in treating cancer, but it often comes with the unfortunate side effect of damaging healthy tissues. This damage is largely due to the production of reactive oxygen species (ROS), which can cause cellular injury. In this chapter, we dive into the world of radioprotectors and mitigators—substances that aim to protect healthy cells while still allowing radiation to effectively target cancer cells. One of the most well-known radioprotectors is amifostine, the only FDA-approved option. It works by neutralizing free radicals and reducing toxicity, but its use is limited due to side effects and the need for intravenous administration. Vitamin C, renowned for its antioxidant properties, has shown promise in protecting organs from radiation damage, though finding the right dosage is still a challenge. Another fascinating compound is curcumin, derived from turmeric. It serves a dual purpose: protecting healthy cells while making cancer cells more vulnerable to radiation. However, its clinical use is hindered by its poor bioavailability, and much research is underway to improve how the body absorbs it. Similarly, hesperidin, a flavonoid found in citrus fruits, has shown potential in protecting the lungs and liver from radiation injury. One of the more interesting compounds is melatonin, a hormone best known for regulating sleep cycles. Beyond that, it has anti-inflammatory and antioxidant effects, which could contribute to its radioprotective properties. An ideal radioprotector would effectively shield normal cells from damage without hindering the radiation’s ability to kill cancer cells. Achieving this delicate balance depends on factors like how the substances are taken up by cells, how they’re activated, and the unique environments in normal versus cancerous tissues. While animal studies have shown these substances hold promise, more rigorous clinical trials are needed to fully establish their safety, effectiveness, and real-world potential. This chapter highlights the latest advances in radioprotective strategies and the hope they bring for improving cancer treatments. If research continues to progress, we could see major breakthroughs in cancer care, helping reduce side effects and improve the overall quality of life for patients undergoing radiotherapy.