We describe the advancing knowledge of fusion cross sections from 1934 through the development of the first thermonuclear tests fielded by Los Alamos (the singular entity denoted Los Alamos Laboratory/Los Alamos Scientific Laboratory/Los Alamos National Laboratory at different times is designated “Los Alamos” in this paper) in the Pacific in 1951–1952; this technical history has not been previously documented. We compare these nuclear reaction cross sections to the current state of their knowledge as codified in the Evaluated Nuclear Data File (ENDF) databases, focusing on the Big Five reactions: 3H ( d , n ) 4 He, 3He ( d , p ) 4 He, 2H ( d , n ) 3 He, 2H ( d , p ) 3 H, and 3H ( t , 2 n ) 4 He. At Oppenheimer’s July 1942 University of California, Berkeley, “galaxy of luminaries” conference, Konopinski suggested that the cross section for 3H ( d , n ) 4 He “DT” could be large, and although Teller described this as an “inspired guess,” we provide evidence instead suggesting that Konopinski knew of a 1938 measurement by Ruhlig that secondary DT reactions were “exceedingly probable.” Bethe’s direction that the DT cross section should be measured at Purdue University (Purdue) in 1943 led to the remarkable and unexpected finding that the DT cross section exceeds deuteron-deuteron (DD) by a factor of 100. This was a game-changing result, making Teller’s dream, i.e., the terrestrial production of fusion energy, feasible. Eyewitness accounts are transcribed from the earliest discoveries of the large magnitude of the resonant DT cross section. A description is given of the Manhattan Project’s early 1942–1944 DD measurements at the University of Chicago, the 1943 DT measurements at Purdue, and the subsequent 1945–1946 DD and DT measurements at Los Alamos. The Los Alamos experiments, led by Bretscher, were the first to extend to very low incident ion center-of-mass energies in the 6- to 50-keV range needed in applications and the first to identify, characterize, and document the 3/2+ “Bretscher state” responsible for the resonance-enhanced DT cross section. The early measurements were based on thick-target experiments that required a knowledge of hydrogen-isotope stopping powers, much of which was informed by 1930s German studies. We end with the high-accuracy APSST (named for Arnold, Phillips, Sawyer, Stovall, and Tuck) measurements at Los Alamos, 1951–1952. The very first 1942–1946 measurements were accurate to about 50% or somewhat better, but by the early 1950s, the cross sections were determined much more accurately, to within a few percent of our best values today, which come from R-matrix Energy Dependent Analysis (EDA) code analyses of the data, most notably the very accurate 1980s–1990 Los Alamos DT and DD fusion data from Jarmie and Brown. We show that Fermi, in his 1945 Los Alamos lectures, anticipated the S-factor (for the DT cross section), which is a concept widely used later in nuclear astrophysics. To this long abstract, we add a final tidbit: Marshall Holloway, a coauthor on the first-ever 1943 DT cross-section measurement at Purdue, went on to lead the engineering and fabrication of the first H-bomb test, Ivy Mike.