The end of the Cold War led to a reduced concern for a major nuclear event. However, the current threats from terrorism make a radiologic (dispersal or use of radioactive material) or nuclear (improvised nuclear device) event a possibility. The specter and enormousness of the catastrophe resulting from a state-sponsored nuclear attack and a sense of nihilism about the effectiveness of a response were such that there had been limited civilian medical response planning. Although the consequences of a radiologic dispersal device are substantial, and the detonation of a modest-sized (10 kiloton) improvised nuclear device is catastrophic, it is both possible and imperative that a medical response be planned. To meet this need, the Office of the Assistant Secretary for Preparedness and Response in the Department of Health and Human Services, in collaboration within government and with nongovernment partners, has developed a scientifically based comprehensive planning framework and Web-based “just-in-time” medical response information called Radiation Event Medical Management (available at www.remm.nlm.gov). The response plan includes (1) underpinnings from basic radiation biology, (2) tailored medical responses, (3) delivery of medical countermeasures for postevent mitigation and treatment, (4) referral to expert centers for acute treatment, and (5) long-term follow-up. Although continuing to evolve and increase in scope and capacity, current response planning is sufficiently mature that planners and responders should be aware of the basic premises, tools, and resources available. An effective response will require coordination, communication, and cooperation at an unprecedented level. The logic behind and components of this response are presented to allow for active collaboration among emergency planners and responders and federal, state, local, and tribal governments.