In the fall of 1942, the United states government asked E. I. du Pont de Nemours and Company to participate in the Manhattan project, a multi-component effort to develop the atomic bomb. The company's initial task was to serve as a subcontractor to aid Stone and Webster in the design and construction of a plutonium separation plant. When General Leslie Groves became Director of the Manhattan Project, he requested the Du Pont Company to play a much more central role in the plutonium project being coordinated by physicists Arthur Compton and Enrico Fermi at the University of Chicago. In December 1942, Du Pont signed an agreement to design and construct a pilot plant-sized reactor and separation works, as well as to operate the plutonium production and separation facilities that were to be located in eastern Washington. This plant became known as the Hanford Engineering Works.

The Hanford Works project, with its 40,000 employees, was placed in the Du Pont Company's existing organization structure. The Executive Committee created a new division (TNX) within the Explosives Department and put it under the direction of Assistant General Manager Roger Williams. Crawford Greenewalt, who would become President of the Du Pont Company after World War II, was asked to serve as a director of the TNX Division's R and D unit and as liaison with the scientists at the university of Chicago's Metallurgical Laboratory. still sensitive about the "Merchant of Death" label thrust upon it by the Nye Committee after World War I, Du Pont committed itself to carrying out the work at cost and, for legal purposes, an annual fee of one dollar.

Less than ten months after signing its initial contract, the Du Pont Company completed the pilot-scale reactor at the Clinton Engineering Works near Oak Ridge, Tennessee. By the following spring, Clinton was shipping significant quantities of plutonium to the Los Alamos (New Mexico) laboratory where the atomic bomb was being designed and built. By early 1945, the Hanford Engineering Works had produced enough plutonium to assemble the bombs tested at Alamogordo, New Mexico, and detonated over Nagasaki, Japan.

Du Pont always envisioned its atomic energy program as a temporary war-time commitment. The Company made it clear that it intended to withdraw from its government contract when it expired in May, 1946. At General Leslie Groves' request, this deadline was extended to December 31. Company officials suggested that Groves recruit the General Electric Company to run Hanford Engineering Works beginning in 1947. After some initial hesitation, General Electric took over the plant in early 1948.

Less than one year later, the Atomic Energy Commission (AEC) asked Du Pont to undertake a survey "of all chemical activities bearing on the manufacture of plutonium." This survey was completed during the summer of 1949. In 1950, the Korean War propelled the Company back into the nuclear field when the AEC and President Harry S. Truman asked Du Pont Company President Crawford Greenewalt to assume responsibility for the design, construction, and operation of a plant which would produce the new generation of atomic materials to be used for the hydrogen bomb. This operation, which became known as the Savannah River Project (SRP), was to be situated in Aiken, South Carolina.

As with Hanford, the Du Pont Company incorporated the Savannah River project within its existing organization structure, establishing an Atomic Energy Division within the Explosives Department. Du Pont designed, developed, constructed, and managed the SRP site at cost, plus a fee of $1 per year. The Engineering Department's Atomic Energy Design Group had primary responsibility for the design and construction of the Savannah River facility. A Construction Division was created to supervise the actual building of the facilities, while a Process section was established to act as liaison between the Construction Division and reactor designers. This section also was responsible for quality control. During the construction period, the Du Pont Company made extensive use of subcontractors. The most prominent were New York Shipbuilding Company, American Machine and Foundry Company, All States Engineering, and the Lummus Company.

Once these organizational issues had been sorted out, Du Pont proceeded to assemble a work force of nearly 40,000. The first priority was the construction of the Heavy-Water Production Plant (400D area). Next, a site was prepared for the building of five nuclear reactors (100 area) and two chemical separation plants (200 area). Facilities to manufacture nuclear fuels were then built in order to provide the products needed to charge the reactors. Finally, research laboratories, administrative offices, worker housing, and other ancillary services were provided for.

By the end of 1955, five reactors and two separations plants were producing plutonium and tritium for United States' nuclear arsenal. As construction gave way to operation, two principal organizations were established to coordinate the start-up of the process facilities: the Production Department and the Works Technical section. The Production Department was in charge of operating the units. The Works Technical section, with engineers, chemists, and physicists, had responsibility for technical, scientific, and safety issues. Finally, a Health Physics Department was created in order to measure the effects of radiation and radioactive materials on people and the environment.

From the beginning, the Atomic Energy Commission and the Du Pont Company recognized they would have to deal with the problem of waste management. Initially, a series of underground waste tanks were built, but these were viewed as a temporary solution. During the early 1960s, Du Pont Company engineers studied the feasibility of constructing a series of caverns underneath the plant, but this proved to be impossible. Later in the decade, there was an effort to develop a Bedrock waste Storage facility, but this also had to be abandoned because of environmental concerns and political opposition. During the 1970s, work began on a Defense Waste Processing Facility that was to convert the radioactive waste products in the underground tanks into a solid form. After more than a decade of research and development, construction of this facility was completed in 1989.

On March 31, 1989, the Du Pont Company relinquished responsibility for the Savannah River site, turning over the management to the Westinghouse Corporation.