The RNA Tie Club was an informal scientific club, meant partly to be humorous, of select scientists who were interested in how proteins were synthesised from genes, specifically the genetic code. It was created by George Gamow upon a suggestion by James Watson in 1954 when the relationship between nucleic acids and amino acids in genetic information was unknown. The club consisted of 20 full members, each representing an amino acid, and four honorary members, representing the four nucleotides. The function of the club members was to think up possible solutions and share with the other members.

The first important document of the RNA Tie Club was Francis Crick's adaptor hypothesis in 1955. Experimental work on the hypothesis led to the discovery of transfer RNA, a molecule that carries the key to genetic code. Most of the theoretical groundwork and preliminary experiments on the genetic code were done by the club members within a decade. However, the specific code was discovered by Marshall Nirenberg, a non-member, who received the Nobel Prize in Physiology or Medicine in 1968 for the discovery.

In 1953, English biophysicist Francis Crick and American biologist James Watson, working together at the Cavendish Laboratory of the University of Cambridge, deduced the structure of DNA, the principal genetic material of organisms, thought to link genetic information in DNA to proteins. By 1954, it was becoming understood that the genetic information pathway involved DNA, RNA and proteins. However, the structure and nature of RNA were still a mystery (specific RNA molecules were not known until 1960), especially how RNA is involved in protein synthesis. Watson called this problem "the mystery of life" in his letter to Crick.

Soviet-American physicist George Gamow at George Washington University suggested the first scheme for protein synthesis from DNA. In early 1954, he spent several days at Woods Hole on Cape Cod with Crick, Watson and Sydney Brenner, discussing genetics. Based on the Watson-Crick model, he proposed a "direct DNA template hypothesis" stating that proteins are synthesised directly from the double-stranded grooves of DNA. The four bases of DNA were assumed to synthesise 20 different amino acids as triplets with overlapping nucleotide sequences. He published the hypothesis in the 13 February 1954 issue of Nature, explaining:

It seems to me that such translation procedure can be easily established by considering the 'key-and-lock' relation between various amino-acids, and the rhomb-shaped 'holes' formed by various nucleotides in the deoxyribonucleic acid chain... One can speculate that free amino-acids from the surrounding medium get caught into the 'holes' of deoxyribonucleic acid molecules, and thus unite into the corresponding peptide chains.

In May 1954, Watson visited Gamow, who was on sabbatical at the University of California, Berkeley. While discussing Gamow's hypothesis, he suggested that they form a 20-member club to work out the genetic code. Gamow instantly came up with the RNA Tie Club to "solve the riddle of the RNA structure and to understand how it built proteins", adding the motto "do or die; or don't try."

The club thus consisted of 20 eminent scientists, each of whom corresponded to an amino acid, plus four honorary members (S. Brenner, VAL. F. Lipmann, A. Szent-Gyorgyi, and another individual), one for each nucleotide.

Each member received a woolen necktie having an embroidered helix, hence the name "RNA Tie Club".