At the end of the 19th century, the Brooklyn Institute of Arts and Sciences founded a biological laboratory for training high school and college teachers in marine biology. As biologists of that time worked out the consequences of Darwin’s theory of evolution, they often established their laboratories at the seashore, where there was an abundance of animals and plants for study. It is not surprising, then, that the Brooklyn Institute looked to the north shore of Long Island for a site for its biological laboratory.

In 1889, John D. Jones gave land and buildings—formerly part of the Cold Spring Whaling Company on the southwestern shore of Cold Spring Harbor—to the Institute. The first course at the new Biological Laboratory (the General Course on Biology) began on July 7, 1890, establishing education in the biological sciences as the Laboratory’s first mission.

Soon, another mission was established: research in genetics. This grew out of two events: the appointment, in 1898, of Charles Davenport, professor of evolutionary biology at Harvard, as director of the Laboratory, and the rediscovery in 1900 of Mendel’s work, carried out 35 years earlier. Mendel’s Laws provided explanations for the variability that underlies evolution, and his work opened new possibilities for experimentation in biology.

Davenport approached the Carnegie Institute of Washington and proposed that it establish a genetics research program at the Cold Spring Harbor site. In June 1904, the Carnegie Institute's Station for Experimental Evolution, later renamed the Department of Genetics, was formally opened by Hugo de Vries, one of the three re-discoverers of Mendel’s work. Scientists at the Brooklyn Institute's Biological Laboratory and the Carnegie Institute of Washington's Department of Genetics continued to work side-by-side at Cold Spring Harbor in this capacity until 1962.

Scientists investigating evolution studied a variety of organisms. George Shull, in his studies of corn, achieved the first great discovery at Cold Spring Harbor in 1908. By studying the growth and yields of corn plants, he found that crossing purebred lines produced hybrid offspring that were more productive. Shull’s discovery led to increased corn production and to a revolution in crop breeding.

In 1916, Clarence Little—studying the genetics of cancer in mice—discovered that Japanese “waltzing” mice, but not other mouse strains, were susceptible to transplanted sarcomas (connective tissue cancers). Little went on to found the Jackson Laboratory in Bar Harbor, Maine (which today is a premier mouse genetics research facility and laboratory supplier). In 1928, E. Carleton MacDowell discovered a strain of mice predisposed to spontaneous leukemia. Subsequent breeding experiments lead to the development of mice with increased susceptibility or resistance to the cancer. McDonnell's work is a cornerstone of modern cancer research.

In 1924, Charles Davenport appointed Reginald Harris as director of the Biological Laboratory. Harris began to change the Laboratory’s research program to focus on quantitative biology—physiology and biophysics in particular. Harris’ greatest legacy was his creation of the Cold Spring Harbor Symposium on Quantitative Biology in 1933.

The appointment in 1941 of Milislav Demerec as director of both the Biological Laboratory and the Department of Genetics signaled a new era of genetics research, one in which microorganisms were used to study the nature of the gene. Demerec began to study of bacteria and bacteriophages, and in 1945 encouraged Max Delbrück to initiate the first advanced course at the Laboratory—the Phage Course. Delbrück and collaborators including Salvador Luria introduced other researchers to these new genetic tools.

The Phage Course played a key role in the development of molecular genetics. Many scientists who took it went on to help determine the physical basis of the gene. Delbrück and Luria were awarded the Nobel Prize in 1969 together with a third phage geneticist, Alfred Hershey, who later made Cold Spring Harbor Laboratory his scientific home. Luria was also James Watson's graduate school mentor, and "growing up in the Phage Group" had a defining influence on Watson’s future.

In 1942, Demerec appointed Barbara McClintock to the Department of Genetics. At that time, she was already acknowledged as a world leader in cytogenetics (the microscopic study of chromosome structure and behavior). In 1944, she became the third woman elected to the National Academy of Sciences. In the 1940s, McClintock began to study puzzling unstable mutations in maize, an effort that ultimately led her to describe transposable elements. In 1983, McClintock received the Nobel Prize for her studies of transposable elements.

During World War II, Milislav Demerec performed other research at the Laboratory which led to isolation of mutant strains of the fungus Penicillium chrysogenum. This research greatly increased the yield of the antibiotic penicillin, used by the U.S. Government for the war effort.
Alfred Hershey came to Cold Spring Harbor in 1950. Two years later, he and Martha Chase performed one of the most famous experiments in modern biology, the “Waring blender” experiment, which reinforced the findings of other scientists that genes were made of DNA, not protein. The discovery of the structure of DNA in 1953, first described publicly by James Watson at the 1953 Cold Spring Harbor Symposium entitled “Viruses,” heralded a new era in biology.

In 1962, the Department of Genetics, no longer supported by the Carnegie Institute of Washington, merged with the Biological Laboratory to form "Cold Spring Harbor Laboratory of Quantitative Biology." (In 1970, the name was simplified to Cold Spring Harbor Laboratory.) The first years of the new institution were financially difficult, and it was only through the heroic efforts of then-director John Cairns that the Laboratory’s financial situation was stabilized. In 1968, Cairns resigned to return to research, and Nobel laureate James Watson, then a professor at Harvard University, agreed to become director while initially retaining his Harvard post.

Watson was eager to change the focus of the Laboratory to the study of cancer. One of his early accomplishments was the 1969 hiring of a young virologist, Joe Sambrook, to begin a tumor virus group that continues today. It was not until 1973, however, that real financial stability came to Cold Spring Harbor Laboratory. In that year, Charles Sammis Robertson established the Robertson Research Fund with a generous gift of nearly $8 million. In 1976, Robertson donated his nearby Banbury Estate to the Laboratory, where it established the Banbury Conference Center in 1977.

Since the 1970s, the Laboratory’s studies on cancer have flourished, and there has been a large expansion and broadening of its research. The study of plants at the Laboratory was reinvigorated in the 1980s with the construction of Page Laboratory, a building dedicated to plant biology. In 1990, the program of neuroscience research at CSHL was significantly expanded with the completion of the Arnold and Mabel Beckman Laboratory.

In addition to the expansion of research at the Laboratory, educational programs at the Laboratory flourished under Watson’s directorship. Major developments in the educational mission of the Laboratory under Watson include the establishment of a large number of postgraduate courses including the seminal Yeast Genetics course, and the founding of the DNA Learning Center in 1988, the first science center devoted entirely to educating the public about genetics. Cold Spring Harbor Laboratory’s long tradition of education in the biological sciences culminated with its accreditation, in 1998, as a Ph.D. degree-granting institution. The founding of the Watson School of Biological Sciences in 1998 and the establishment of the CSHL Cancer Genome Research Center just two years later is a clear demonstration of how education and research have progressed together at Cold Spring Harbor Laboratory since its inception.

In 1994, CSHL scientist Bruce Stillman became director of the Laboratory and Watson became its president. Stillman, a pioneer in the field of DNA replication who has worked at the Laboratory since 1979, was elected a Fellow of the Royal Society (London) in 1993 and a member of the U.S. National Academy of Sciences in 2000.

In 2003, Watson became chancellor and Stillman was named president of Cold Spring Harbor Laboratory. Stillman also seves as chief executive officer of the Laboratory and as director of its NCI-designated Cancer Center.

In 2007 Watson retired as chancellor, and in 2008 he was appointed chancellor emeritus.