The University of North Carolina at Chapel Hill announced Smithies' death Wednesday.
University spokeswoman MC VanGraafeiland said school officials were told of his death on Tuesday by his wife, Dr. Nobuyo Maeda.
Smithies won the Nobel Prize for developing a technique used to manipulate genes in mice. The advance enhanced genetic research to better understand cancer, obesity, heart diseases and other diseases.
The university said Smithies' lab created the first animal model of cystic fibrosis in 1992.
Smithies shared his 2007 prize with the University of Utah's Mario Capecchi and Sir Martin Evans of Cardiff University in the United Kingdom.