A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses >2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network.