The 1939 discovery of nuclear fission in Germany alarmed the largely-refugee, anti-Nazi physics community: if the Nazis weaponised the same discovery first, the war would go somewhere far worse. In 1939 Einstein and Szilárd wrote to Roosevelt urging the United States to begin research. The American response was initially modest, but after Pearl Harbor in December 1941 the budget was lifted.

In August 1942 the Manhattan Engineer District was formally established — the code name came from the project's first office in New York's Manhattan borough. General Leslie Groves took command and the physicist J. Robert Oppenheimer became scientific director. Three main sites: Oak Ridge, Tennessee, for uranium-235 enrichment; Hanford, Washington, for plutonium production; Los Alamos, New Mexico, for weapon design. At peak the project employed roughly 130,000 people; total cost was about 28 billion dollars in today's money.

On 2 December 1942, beneath the disused racquets court at the University of Chicago, Fermi's team brought the graphite-uranium pile CP-1 to criticality. A controlled chain reaction ran for 28 minutes — and a coded message left the lab: "The Italian navigator has landed in the New World." That moment marked a new age that began not in the radioactive nuclei within the Earth's mantle but in a reactor humans had themselves built.

On 16 July 1945 the Trinity test was conducted in the New Mexico desert. Three weeks later the bombs dropped on Hiroshima and Nagasaki killed some 200,000 people. The war ended; the Cold War began. The Manhattan Project gave birth to more than a weapon: it produced a new relationship between state, science and industry — the "Big Science" era that would model the Apollo programme, particle accelerators, and the Human Genome Project.