In 1951, when the American biologist James Watson arrived at the laboratory, it was known that the mysterious nucleic acids, especially DNA, played a central role in the hereditary determination of the structure and function of each cell. Watson convinced Crick that knowledge of DNA's three-dimensional structure would make its hereditary (genetics) role apparent. Using the X-ray diffraction studies of DNA done by Wilkins and X-ray diffraction pictures produced by Rosalind Franklin (Franklin, Rosalind), Watson and Crick were able to construct a molecular model consistent with the known physical and chemical properties of DNA. The model consisted of two intertwined helical (spiral) strands of sugar-phosphate, bridged horizontally by flat organic bases. Watson and Crick theorized that if the strands were separated, each would serve as a template (pattern) for the formation, from small molecules in the cell, of a new sister strand identical to its former partner. This copying process explained replication of the gene and, eventually, the chromosome, known to occur in dividing cells. Their model also indicated that the sequence of bases along the DNA molecule spells some kind of code (genetic code) “read” by a cellular mechanism that translates it into the specific proteins responsible for a cell's particular structure and function.

By 1961 Crick had evidence to show that each group of three bases (a codon) on a single DNA strand designates the position of a specific amino acid on the backbone of a protein molecule. He also helped to determine which codons code for each of the 20 amino acids normally found in protein and thus helped clarify the way in which the cell eventually uses the DNA “message” to build proteins. From 1977 until his death, Crick held the position of distinguished professor at the Salk Institute for Biological Studies in San Diego, California, where he conducted research on the neurological basis of consciousness. His book Of Molecules and Men (1966) discusses the implications of the revolution in molecular biology. What Mad Pursuit: A Personal View of Scientific Discovery was published in 1988. In 1991 Crick received the Order of Merit.