Smith, Hamilton Othanel (1931-) is an American microbiologist who made breakthrough discoveries related to enzymes, the molecules that speed up the chemical reactions in all living things. He shared the 1978 Nobel Prize in physiology or medicine with Werner Arber and Daniel Nathans for discoveries in molecular genetics.

Smith received his undergraduate degree in mathematics from the University of California, Berkeley, in 1952, and earned his M.D. degree at Johns Hopkins University School of Medicine in Baltimore in 1956. In 1962, he received a post-doctoral fellowship from the National Institutes of Health to do genetics research at the University of Michigan. He returned to Johns Hopkins University in 1965 as a research associate in the microbiology department. He became a full professor of microbiology in 1973 and, in 1981, professor of molecular biology and genetics.

Smith first became aware of restriction enzymes, enzymes that are able to break strands of dioxyribonucleic acid (DNA) into smaller pieces, in the 1960's. Arber, a Swiss microbiologist, had found restriction enzymes that could recognize specific DNA sequences but were incapable of severing only those recognized segments. Instead, these so-called type I restrictive enzymes would break the gene in random and unpredictable places.

In 1968, Smith purified an enzyme that seemed to exhibit characteristic restriction enzyme behavior. The following year he determined that this purified enzyme, now known as type II restrictive enzymes, was able to not only recognize a specific DNA sequence but to sever only the recognized segment.

This discovery allowed microbiologists to determine the precise order of genes on chromosomes, to analyze the chemical structure of genes, and to create new combinations of genes, the results of which are known as recombinant DNA.