In 1980, Congress created the Agency for Toxic Substances and Disease Registry (ATSDR) to implement the health-related sections of laws that protect the public from hazardous wastes and environmental spills of hazardous substances. The Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), commonly known as the "Superfund" Act, provided the Congressional mandate to remove or clean up abandoned and inactive hazardous waste sites and to provide federal assistance in toxic emergencies. As the lead Agency within the Public Health Service for implementing the health-related provisions of CERCLA, ATSDR is charged under the Superfund Act to assess the presence and nature of health hazards at specific Superfund sites, to help prevent or reduce further exposure and the illnesses that result from such exposures, and to expand the knowledge base about health effects from exposure to hazardous substances.

In 1984, amendments to the Resource Conservation and Recovery Act of 1976 (RCRA), which provides for the management of legitimate hazardous waste storage or destruction facilities, authorized ATSDR to conduct public health assessments at these sites, when requested by the Environmental Protection Agency (EPA), states, or individuals. ATSDR was also authorized to assist EPA in determining which substances should be regulated and the levels at which substances may pose a threat to human health.

With the passage of the Superfund Amendments and Reauthorization Act of 1986 (SARA), ATSDR received additional responsibilities in environmental public health. This act broadened ATSDR's responsibilities in the areas of public health assessments, establishment and maintenance of toxicologic databases, information dissemination, and medical education.