Hazardous chemical, radiological, and nuclear materials threaten public health in scenarios of accidental or intentional release which can lead to external contamination of people. Without intervention, the contamination could cause severe adverse health effects, through systemic absorption by the contaminated casualties as well as spread of contamination to other people, medical equipment, and facilities. Timely decontamination can prevent or interrupt absorption into the body and minimize opportunities for spread of the contamination, thereby mitigating the health impact of the incident. Although the specific physicochemical characteristics of the hazardous material(s) will determine the nature of an incident and its risks, some decontamination and medical challenges and recommended response strategies are common among chemical and radioactive material incidents. Furthermore, the identity of the hazardous material released may not be known early in an incident. Therefore, it may be beneficial to compare the evidence and harmonize approaches between chemical and radioactive contamination incidents. Experts from the Global Health Security Initiative’s Chemical and Radiological/Nuclear Working Groups present here a succinct summary of guiding principles for planning and response based on current best practices, as well as research needs, to address the challenges of managing contaminated casualties in a chemical or radiological/nuclear incident.