On December 6, 1941, just one day before the attacks on Pearl Harbor, President Roosevelt expanded the program again. Project S-1 was to have improved financial and administrative support from high ranking government officials. James Conant, who had taken over as head of the NDRC following the creation of the OSRD, took a stance of strong support for the program. Throughout the remainder of the war, he would serve as an important scientific advisor for nuclear research in the U.S. Project S-1, now under the OSRD, was headed by Arthur H. Compton and involved many prominent scientists such as Harold Urey and E. O. Lawrence. From late 1941 until the spring of 1942, the members of S-1 worked to further define the properties of uranium and the means of manufacturing it.

By 1942 the American nuclear effort was fully operational. With Oppenheimer serving as the chief theorist at S-1 and Enrico Fermi - famed physicist and radiation expert - building a nuclear reactor at the University of Chicago, the program was progressing rapidly. Due to the need for security and the construction of large facilities, the U.S. Army Corps of Engineers took control of the nuclear program in August. Colonel James C. Marshall was charged with heading the operation. In mid-August he moved to New York City, famously changing the project's codename from the Laboratory for the Development of Substitute Metals, to the Manhattan Engineer District (MED). The project, which had long been run by civilian scientists, was now a joint operation, with the S-1 scientists continuing their research while all administrative work was run directly by the U.S. military.

The transition between OSRD and Army control was not without problems. Marshall was cautious and preferred to move slowly, delaying the construction of facilities and the procurement of key materials. At Bush's urging, it was decided that Marshall should be replaced with a more dynamic administrator. On September 17, 1942, Colonel Leslie Groves was given command of the Manhattan Engineer District. Groves was an experienced administrator. He had personally overseen the construction of the Pentagon, an immense and complicated project that had taught him the importance of organization and decisiveness. While the scientists of the Manhattan Project found him to be overbearing, he was able to quickly resolve many of the issues that had impeded progress during Compton and Marshall's time as administrators.