Smith and Hutchison introduced site-directed mutagenesis, or oligonucleotide-directed mutagenesis, into molecular biology, resolving the problem of how to determine the effect of a single mutant gene with efficiency. They developed a synthetic DNA technique for introducing site-specific mutations into genes. This permitted comparison of different protein molecules, revealing the role of the initial mutation. The technique is used for investigating the structure and biological activity of DNA, RNA, and protein molecules, and for protein engineering.

The new technology enabled rapid identification and deliberate alteration of genes for the purpose of changing the characteristics of an organism. It raised the level of possibility of new diagnostic strategies and new treatments for genetic diseases, and even creation of novel artificial forms of life, as the progenitor technique for polymerase chain reaction (PCR). Digital facsimile from PubMedCentral at this link.

In 1993 Michael Smith was awarded half of the Nobel Prize in Chemistry "for his fundamental contributions to the establishment of oligonucleotide-based, site-directed mutagenesis and its development for protein studies." The other half was awarded to Kary B. Mullis "for his invention of the polymerase chain reaction (PCR) method."