Mass exposure to radiologic substances presents a unique challenge to the entire response effort, which includes health care professionals, law enforcement personnel, and other first responders. Recognition of signs and symptoms of exposure, and focus on removal and decontamination are priorities of management. Radiation injuries require specialized equipment and access to experts. Patients can have complex patterns of injury, ranging from trauma and the immediate results of an explosion or exposure, to progressive damage associated with radiation sickness. Both conventional injury and radiation illness may require critical care management. Remembering the essentials of first response, that is, treat the patient, not the poison, by addressing the ABCs of airway, breathing, and circulation, is critical to appropriate treatment of radiation exposure. Understanding the basic science of radiologic agents will aid the provider in managing affected patients and preventing further casualties.