Since 1946, the Centers for Disease Control and Prevention has responded to urgent requests from US states, federal agencies, and international organizations through epidemic-assistance investigations (Epi-Aids). The authors describe the first 60 years of Epi-Aids, breadth of problems addressed, evolution of methodologies, scope of activities, and impact of investigations on population health. They reviewed Epi-Aid reports and EIS Bulletins, contacted current and former Epidemic Intelligence Service staff, and systematically searched the PubMed and Web of Science databases. They ed information on dates, location, staff involved, health problems, methods, and impacts of investigations according to a preplanned protocol. They assessed the methods presented as well as the quality of reports. During 1946-2005, a total of 4,484 investigations of health events were initiated by 2,815 Epidemic Intelligence Service officers. In the early years, the majority were in response to infectious agents, although environmental problems emerged. Investigations in subsequent years focused on occupational conditions, birth defects, reproductive health, tobacco use, cancer, violence, legal debate, and terrorism. These Epi-Aids heralded expansion of the agency's mission and presented new methods in statistics and epidemiology. Recommendations from Epi-Aids led to policy implementation, evaluation, or modification. Epi-Aids provide the Centers for Disease Control and Prevention with the agility to respond rapidly to public health crises.