Of primary concern to mission planners are the health risks associated with the complex environment of space radiation, which evidence suggests will include cancer, cardiovascular disease, and neurological deficits, in addition to the possibility of acute radiation syndromes. Because shielding cannot eliminate radiation exposures, pharmacological countermeasures might be essential; however, designated agents have yet to be established. Human datasets on the effects of radiation are limited to acute radiation emergencies, clinical radiotherapy, or occupational exposures. Radiation countermeasures used on Earth include agents that intercept free radicals, aid in symptom management, help restore blood cell counts, or prevent opportunistic infections. Some pharmaceuticals and nutraceuticals may prove useful as space radiation countermeasures, but thoughtful experimentation is required to model the complex space radiation environment. Agents can be categorized as radiomodulators (taken prophylactically to increase resistance to radiation-induced damage or mutagenesis), radioprotectants (taken before an acute exposure), and radiomitigators (taken after). Ultimately, a mission’s formulary should be tailored to the quantity and quality of expected radiation exposure (i.e., chronic, low-dose, high-energy, isotropic, and multispecies), with specific deterministic/stochastic and acute/delayed health outcomes in mind. Potential countermeasures must demonstrate safety, efficacy, and stability in spaceflight, and they must meet the biomedical and practical needs of any given mission.