A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA. The loss of gene activity often causes changes in a mouse's phenotype, which includes appearance, behavior and other observable physical and biochemical characteristics.

Knockout mice are important animal models for studying the role of genes which have been sequenced but whose functions have not been determined. By causing a specific gene to be inactive in the mouse, and observing any differences from normal behaviour or physiology, researchers can infer its probable function.

Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied. They are widely used in knockout experiments, especially those investigating genetic questions that relate to human physiology. Gene knockout in rats is much harder and has only been possible since 2003.

Mario Renato Capecchi (Verona, Italy, 6 October 1937) is an Italian-born American molecular geneticist and a co-winner of the 2007 Nobel Prize in Physiology or Medicine for discovering a method to create mice in which a specific gene is turned off (knocked out). He infected embryonic stem cells with a viral vector that was designed to incorporate itself into the target gene by homologous recombination. Homologous recombination is a process that cells normally use to repair their DNA, which is exploited by viruses to infect cells. He shared the prize with Martin Evans and Oliver Smithies. He is currently Distinguished Professor of Human Genetics and Biology at the University of Utah School of Medicine, which he joined in 1973.

Mario Capecchi was born in the Italian city of Verona as the only child of Luciano Capecchi, an Italian airman who would be later reported as missing in action while manning an anti-aircraft gun in the Western Desert Campaign, and Lucy Ramberg, an American-born daughter of Impressionist painter Lucy Dodd Ramberg and German archaeologist Walter Ramberg. During World War II, his mother was sent to the Dachau concentration camp as punishment for pamphleteering and belonging to an anti-Fascist group. Prior to her arrest she had made contingency plans by selling her belongings and giving the proceeds to a peasant family near Bolzano to provide housing for her only child. However, after one year, the money was exhausted and the family was unable to care for him. At four-and-a-half years old he was left to fend for himself on the streets of northern Italy for the next four years, living in various orphanages and roving through towns with groups of other homeless children.