The concept of the therapeutic ratio (TR) is central to understanding the rationale for using radioprotectors. The TR relates tumor control probabilities and normal tissue complication probabilities to one another. An ideal radioprotector will reduce the latter without compromising the former. It should also be minimally toxic itself. Radioprotective strategies can be classified under the categories of protection, mitigation, and treatment. Protectors are administered before radiotherapy (RT) and are designed to prevent radiation-induced injury. Amifostine is the prototype drug. Mitigants are administered after RT but before the phenotypic expression of injury and are intended to ameliorate injury. Palifermin can be considered as the prototype mitigant. Treatment is a strategy that is predominantly palliative and supportive in nature. Pharmacologic radioprotective strategies should be integrated with physical strategies such as intensity-modulated radiotherapy to realize their maximum clinical potential.