Despite the critical acclaim she received for her research, McClintock was frustrated at her long-term job prospects. As she wrote in April 1935, "No sign of a job has turned up for me as yet. I can't say that it makes me feel very peppy to be still in the unemployed list although I am getting a decent salary just now. The uncertainty gets under my skin a bit and hinders my spirits. My work has suffered in consequence without the necessary stimulus." In the spring of 1936, however, her spirits were lifted after Lewis Stadler invited McClintock to become an assistant professor at the University of Missouri at Columbia, where she had conducted research while a postdoctoral fellow five years earlier.

During her time at Missouri, she expanded her research on X-rays and maize. For years, geneticists had been using X-rays to look for genes in fruit flies, maize, and other organisms. The X-rays caused mutations; when these resulted in observable changes in the organism, the geneticist could experimentally map the mutation--and therefore the gene--to a particular site on a chromosome. In some cases, the X-rays physically broke the chromosome, which, McClintock discovered, led to fascinating behavior as the broken ends found one another and fused in different ways. Then, in the late 1930s, among her stocks of X-rayed plants, McClintock discovered plants whose chromosomes broke spontaneously without further irradiation. Further, the breakages continued as the plants grew, in a cycle of breakage, fusion, and "bridge"--as fused chromosomes tugged apart at cell division. McClintock's description of the "breakage-fusion-bridge" cycle in 1938 reaffirmed her status as one of the great figures of maize cytogenetics, as well as giving her a powerful tool for deeper research into the chromosome. This work engaged her wholehearted. As she wrote to a colleague in August 1940, "Have been working like hell on an exciting over-all problem in genetics with wonderful results. It gets me up early and puts me to bed late!"

Although faculty and administration alike recognized the importance of her research, McClintock was increasingly frustrated by her position at Missouri. She believed that there was "inadequate opportunity for advancement," especially since support for women at U.S. universities was--and, to a certain degree, remains--notoriously precarious. In September 1940, McClintock wrote to Charles Burnham, "I have decided that I must look for another job. As far as I can make out, there is nothing more for me here. I am an assistant professor at $3,000 and I feel sure that that is the limit for me." McClintock decided to leave Missouri. In the summer 1941, she arranged to visit Columbia University, where her Cornell colleague Marcus Rhoades was a professor, and he offered to share his research plot at Cold Spring Harbor on Long Island. In December of that year, Milislav Demerec, the new Director of Cold Spring Harbor and a Drosophila expert, offered her a one-year position at the Carnegie Institution's Department of Genetics, which was made permanent the following spring.