Smithies discovered, simultaneously with Mario Capecchi and Martin Evans, the technique of homologous recombination of transgenic DNA with genomic DNA, a much more reliable method of altering animal genomes than previously used, and the technique behind gene targeting and knockout mice.

In 2007 Smithies shared the Nobel Prize in Physiology or Medicine with Mario R. Capecchi and Martin J. Evans "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells."
Order of authorship of the original publication: Doetschman, Gregg...Smithies.